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Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye

  • Kuei-Ju Cheng
    Kuei-Ju Cheng
    School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
    Department of Pharmacy, Taipei Municipal Wanfang Hospital, Taipei Medical University, No. 111, Section 3, Xing-Long Road, Taipei 11696, Taiwan
  • Chien-Ming Hsieh
    Chien-Ming Hsieh
    School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
  • Kunal Nepali*
    Kunal Nepali
    School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
    *K.N.: E-mail: [email protected]
    More by Kunal Nepali
  • , and 
  • Jing-Ping Liou*
    Jing-Ping Liou
    School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
    *J.-P.L.: Phone, 886-2-27361661 ext 6130; email, [email protected]
Cite this: J. Med. Chem. 2020, 63, 19, 10533–10593
Publication Date (Web):June 2, 2020
https://doi.org/10.1021/acs.jmedchem.9b01033
Copyright © 2020 American Chemical Society
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Abstract

The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure sealant to seal corneal incisions, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. A literature survey also indicates that gene therapy, stem cell therapy, and target discovery through genomic research represent significant promise as potential strategies to achieve tissue repair or regeneration and to attain therapeutic benefits in ocular diseases. Overall, the emergence of new technologies coupled with first-in-class entries in ophthalmology are highly anticipated to restructure and boost the future trends in the field of ophthalmic drug discovery. This perspective focuses on various aspects of ocular drug discovery and the recent advances therein. Recent medicinal chemistry campaigns along with a brief overview of the structure–activity relationships of the diverse chemical classes and developments in ocular drug delivery (ODD) are presented.

1. Introduction

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The eye, an organ of the visual system, has a complex anatomical structure produced from the coordinated development of multiple tissues (Figure 1).(1) Disruption of the ocular tissues leads to visual impairment, and vision loss significantly affects the ability of an individual to maintain their independence and deteriorates the quality of life.(2,3) Damage to the retina and optic nerve along with aging stand out as the major causes of visual impairment.(4,5) At present, the health care system is dealing with visual impairment as a major challenge. Recent fact sheets by the WHO indicate that 1.3 billion people have vision impairment, the majority of whom are over the age of 50 years.(6) This particular fact, coupled with the continuing improvement in the health care sector that has led to an increased lifespan, indicates that a substantial proportion of the world’s population will incur the risk of developing some kind of visual impairment.(4) In this context, a better understanding of ocular diseases to fabricate and implement potential strategies to enable earlier detection and treatment is needed.

Figure 1

Figure 1. Anatomy of eye.

Age-related macular degeneration (AMD), cataracts, diabetic retinopathy (DR), dry eye (DE), and glaucoma represent common ocular diseases.(5) Literature reports indicate that a significant amount of work has been done in the past decade to develop ocular therapeutics at both the preclinical and clinical levels in the academic and industrial sectors. Recent developments in the field of ophthalmology include multidirectional success at the clinical level, as FDA approvals were not just confined to small molecular weight therapeutics(7−9) but also included fixed dose combination (FDC),(10,11) gene therapy,(12) ocular sealant,(13) as well as antibody fragment (single chain) inhibitor of vascular endothelial growth factor (VEGF).(14) Furthermore, modern ocular drug delivery (ODD) systems have enormously advanced through the implementation of ocular inserts,(15) punctum plugs,(16) micro-intraocular implants,(17) hydrogels,(15) contact lenses,(18) liposomes,(19) ocular rings,(20) nanoparticles,(21) and novel emulsion technologies,(22) among others. In addition to the efforts at the clinical stage, medicinal chemists have been quite proficient in designing new chemical architectures for furnishing ocular drugs, employing robust drug design strategies as part of preliminary investigations. These interesting attempts have not only yielded potent hits and leads but also provided useful insights for scaffold selections, substituent installations and other subtle structural variations to generate potent agents.(23−30) Overall, the emergence of new technologies coupled with new first-in-class entries in ophthalmology is likely to boost future trends in the field of ophthalmic drug discovery.
In this review, we present various aspects of ocular drug discovery and the recent advances therein. Specifically, this compilation emphasizes the preclinical development of ocular drugs and summarizes the therapeutic value of emerging classes of drugs that have demonstrated potential to replicate the initial promise at higher-stage investigations. In addition, an update on the clinical status of gene therapies and small-molecule ocular therapeutics is presented. Recent medicinal chemistry campaigns with a brief overview of the structure–activity relationships of the diverse classes endowed with substantial promise for the treatment of ocular diseases are included. This perspective also covers innovations in drug delivery methods, systems to traverse ocular barriers, and a brief discussion on the physicochemical properties of drugs affecting ODD.

2. Ocular Diseases

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2.1. Age-Related Macular Degeneration (AMD)

AMD occurs due to an abnormality of the retinal pigment epithelium (RPE) and causes damage to the macula.(31,32) AMD is considered to be a leading cause of central vision loss in patients aged 65 or over.(33) Risk factors have been recognized for the prevalence of AMD, and age is considered to be the strongest risk factor among them.(34) Individuals with a positive family history of AMD are at high risk, and the affected individual’s siblings are 3–6-fold more prone to develop AMD in comparison to the general population. AMD also has a strong genetic component.(35,36) Different gene variants on chromosomes 1, 6, and 10 have been identified as major culprits in AMD, and these genes play pivotal roles in controlling retinal homeostasis, immune responses, and inflammatory processes.(37) Furthermore, smoking is the most prominent modifiable nongenetic risk factor consistently associated with AMD.(38,39)
Drusen, the characteristic lesions of AMD, are formed due to the buildup of membranous debris under the RPE basement membrane.(40) Clinically, AMD is catergorized as early stage (no vision loss) to late-stage AMD that leads to the loss of vision. The latter is further categorized as geographic atrophy (GA) and choroidal neovascularization (CNV, wet AMD) caused by the abnormal growth of blood vessels (Figure 2).(4,39) The exact underlying mechanism for the development of AMD is still unknown. As such, AMD is a multifactorial disorder, and there is no predominant etiological element responsible; rather, it is a cascade of sequential events generated from interactions of several factors, including metabolic, functional, genetic. and environmental factors, that provide an appropriate environment to flourish its development.(5,39) The key processes involved in the progression of AMD have been suggested to be accumulation of lipofuscin, oxidative damage, abnormal immune system activation, increased apoptosis, or abnormalities in Bruch’s membrane.(41) Particularly in CNV, VEGF-A has been implicated, as increased vascular permeability leads to the loss of vision.(42)

Figure 2

Figure 2. (a) Retina diagram by optical coherence tomography: normal retina (top) and a retina with pigmented epithelium detachment (bottom). (b) Normal retina and macula. (c) Macula with confluent soft drusen. (d) Macula of geographic atrophy. (e) Macula (CNV) with hemorrhage. (f) Optic nerve with glaucomatous excavation.(4) Reproduced with permission from ref (4). Copyright 2012 Nature Research.

2.1.1. Treatment in the Clinic and Emerging Targets

2.1.1.1. Anti-VEGF Therapy
Anti-VEGF treatments aim to reduce new blood vessel growth (neovascularization) or edema (swelling). The utilization of this therapy has significantly reduced the prevalence of visual impairment globally.(43) Ranibizumab, bevacizumab, pegatanib, brolucizumab. and aflibercept excellently represent the potential and success of this therapy. Ranibizumab, a recombinant humanized antibody fragment, is an inhibitor of VEGF-A isoforms and is administered intravitreally for the treatment of neovascular AMD. Bevacizumab, a humanized anti-VEGF monoclonal antibody, is used for the treatment of wet AMD. Pegaptanib is anti-VEGF aptamer approved for treating neovascular AMD. Recently, US FDA approved Brolucizumab, another humanized antibody fragment (single chain) inhibitor of VEGF, for the treatment of wet AMD. Aflibercept, a fusion protein also called VEGF trap-eye, has become the mainstay treatment for wet AMD.(14,43,44)
2.1.1.2. Complement Pathway Inhibitors
The complement pathway is implicated in the pathogenesis of many diseases. In particular, association between AMD and genotypic variants of complement pathways has been evidenced.(45,46) Because of the multiple gene associations within the complement activation pathway, a number of inhibitors are currently being evaluated in clinical stage investigations (Table 2).
2.1.1.3. Visual Cycle Inhibitors
Abnormal accumulation of autofluorescent lipofuscin within the RPE is a characteristic early feature of GA. Lipofuscin contains the bisretinoid visual cycle byproduct N-retinylidene-N-retinylethanolamine (A2E), which has several deleterious effects on RPE cells, such as ROS generation, lysosomal function impairment, pro-apoptotic protein induction, and upregulation of VEGF.(47) RPE cell death may be attributed to excessive A2E/lipofuscin accumulation, which ultimately leads to AMD disease progression. Visual cycle modulators target key components of the visual cycle (Figure 3) to prevent cell damage/death in the retina. These agents have garnered considerable attention as a logical strategy to abate the disease progression by reducing accumulation of A2E.(4,48,49)

Figure 3

Figure 3. Mechanism of action: visual cycle inhibitors.

2.1.1.4. Mammalian Target of Rapamycin (mTOR)
mTOR is considered to be a regulator of cell growth and survival. It has been well explored that deregulation of the mTOR signaling pathway leads to several human diseases owing to its involvement in cell proliferation and survival processes. Notably, mTOR has been determined to be a critical factor in the angiogenesis processes of various retinal pathologic conditions.(50) Therefore, several mTOR inhibitors are presently being evaluated at clinical level (Table 2).
2.1.1.5. Stem Cell Therapy
Stem cell therapy appears to be a potential treatment strategy for AMD. In this context, pluripotent stem cell-derived RPE cells were grafted into human subjects in some clinical trials.(51) Different methods have been applied, such as employing induced pluripotent stem (iPSCs) to grow RPE cells that can be transplanted into the patient. Another method involves the utilization of RPE-specific stem cells grown from adult RPE cells (eyes donated to an eye bank).(52) Different methods of stem cell delivery to the eye are also being explored. Recently, RPE cell patches originating from oncogenic mutation-free iPSCs that safely slow the degeneration of the retina in rat and pig models of AMD were designed by Bharti et al. An IND application for a phase I trial has been filed by the research team for this stem cell eye patch for macular degeneration.(53) Another promising delivery approach involves a suspension of cells, derived from iPSCs, RPE stem cells, or human embryonic stem cells, to be injected in eye.(52)
2.1.1.6. Gene Therapy
Gene therapy to chronically express anti-VEGF proteins can substantially reduce the treatment burden of chronic intravitreal therapy.(54,55) Spark Therapeutics’ Luxturna (voretigene neparvovec) for IRD caused by RPE65 gene mutations was the first approved gene therapy in the US.(56) Overall, several ocular gene therapy trials to treat retinal degeneration have been substantially successful.(54−56) The success of gene therapy in IRD has led to the initiation of similar explorations in AMD, although AMD is not associated with a single genetic effects and suffers from a greater societal burden.(57−59) Adeno-associated virus (AAV) is the most extensively utilized viral vector and is considered to be an ideal for gene therapy owing to its excellent safety profile, nonpathogenic nature, and low retinal toxicity as well as its low inflammatory potential.(58) Intravitreal injection or pars plana vitrectomy and subretinal injection represent two potential methods for the delivery to target retinal tissue. At present, the gene therapies in neovascular AMD are being explored to express antiangiogenic proteins [(pigment epithelium derived factor (PEDF), fms-like tyrosine kinase-1 (sFLT-1)].(58) Several gene therapies for AMD are undergoing clinical investigation, such as AdGVPEDF.11D,(60) AVA 001 (AAVsFLt1),(58,61−63) AAV2-SFLT01,(64,65) ADVM-022,(62) RGX-314 (AAV8-AntiVEGF),(66) RetinoStat (EIA Vendostatinangiostatin),(67) and HMR59 (NCT03144999). The highest development phases of these therapies are mentioned in Table 1.(58) In summary, the strategy to deliver DNA into the patient’s cells via a virus can open an avenue leading to its emergence as a future preferred therapy.
Table 1. Gene Therapies in Clinical Stage Investigations(54,59)
TherapyDetails
AdGVPEDF.11Droute: intravitreal
 disease: wet AMD
 vector: AAV
 mechanism of action: cellular expression of VEGF binding receptor FLT1
 highest phase: phase I (completed, NCT00109499)
 company: Avalanche Biotechnologies
 A clinical study in patients with neovascular AMD was conducted and the outcome of the investigation revealed that the single intrevitreous injection with dose >108 PU of AdPEDF.11D exhibited antiangiogenic activity that may last for several months.(60)
       
AAVsFLt1route: subretinal
 disease: wet AMD
 vector: AAV
 mechanism of action: cellular expression of VEGF binding receptor FLT1
 highest phase: phase I/II (completed, NCT01494805)
 company: Avalanche Biotechnologies
 Safety Profile in patients with wet AMD (single sub retinal injection) was evaluated in a single-center, phase 1, randomized controlled trial. No drug-related adverse events were encountered and only mild subconjunctival or subretinal hemorrhage were observed. The outcome of the trial indicated that rAAV.sFLT-1 was safe and well tolerated.(61)
 Safety profile of rAAV.sFlt-1 subretinal injection in wet AMD was assessed (A phase 1 dose escalation trial) and the results demonstrated it was well tolerated and safe throughout the period of 36 months.(58)
 The results of phase 2a clinical trials of AVA-101 conducted in patients with wet AMD were announced by Avalanche Biotechnologies in 2015. AVA-101 was found to be endowed with favorable safety profile and exhibited an improvement on best corrected visual acuity (BCVA). Moreover, a favorable trend in the response rate was also observed.(62)
 Phase 2a randomized controlled trial was performed for subretinal rAAV.sFLT-1 gene therapy in subjects (n = 32) with wet AMD. The results of the study resonated with the phase 1 results as no serious ocular adverse events were observed.(63)
     
AAV2-SFLT01route: intravitreal
 disease: wet AMD
 vector: AAV
 mechanism of action: AAV mediated expression of VEGF binding receptor FLT1
 highest phase: phase I (completed, NCT01024998)
 company: Genzyme (Sanofi)
 Phase 1 study in patients (n = 19) with advanced stage wet AMD for AAV2-sFLT01 was conducted. No dose limiting toxicity was observed and the intravitreal administration of AAV2-sFLT01 was found to be safe. Moreover, a sustained reduction in retinal fluid was observed which indicated a possibility of attaining a sustained therapeutic anti-VEGF level with a single intravitreal administration AAV2-sFLT01.(64)
 Phase 1 study (intravitreous injection) for advanced wet AMD was conducted and the results revealed that AAV2-sFLT01 was safe as well as well tolerated.(65)
       
ADVM-022 (AAV2.7m8, Afilbercept)route: intravitreal
 disease: wet AMD
 vector: AAV.7m8
 mechanism of action: intravitreally delivered gene therapy utilizing proprietary AAV.7m8 vector
 highest phase: phase I (recruiting, NCT03748784)
 company: Adverum Biotechnologies(62)
       
RGX-314 (AAV8-AntiVEGF)route: subretinal
 disease: wet AMD
 vector: AAV8
 mechanism of action: monoclonal antibody binds VEGF
 highest phase: phase I (recruiting, NCT03066258)
 company: Regenxbio(66)
        
RetinoStatsubretinal injection of equine infectious anemia lentivirus
 route: subretinal
 disease: wet AMD
 vector: lentivirus
 mechanism of action: angiogenesis inhibition
 highest phase: phase I completed (NCT01678872, NCT01301443)
 company: Oxford Biomedica
 A phase I study with advanced and recalcitrant neovascular AMD was conducted, and it was observed that the treated eyes were able to sustain a high level of angiostatin and endostatin expression throughout the study. Out of all the subjects, significant reduction in intraretinal/subretinal fluid was observed in only one patient.(67)
       
HMR59 (AAVCAGsCD59)route: intravitreal
 disease: wet and dry AMD
 vector: AAV
 mechanism of action: inhibits the MAC formation through CD59 expression
 highest phase: phase I (recruiting, NCT03585556, wet AMD)
 phase I (active, NCT03144999, dry AMD)
 company: Hemera Biosciences (NCT03144999)
Recent updates on the clinical/preclinical status of agents in AMD are presented in Table 2.
Table 2. Update on Clinical/Preclinical Status of Agents in AMD
Agents/formulation/ClassTarget/ConditionUpdates and other relevant information
Tyrosine Kinase Inhibitors (TKI)
SirolimusAMD, DMESirolimus (mTOR inhibitor)
  phase II, NCT00656643: diabetic macular edema (DME) (completed)
        
RAD-001AMD, CNVRAD-001 (mTOR inhibitor)
  phase II: NCT00304954 (completed)
        
Palomid 529AMDPalomid 529 (TORC1/TORC2 inhibitor)
  phase I: NCT01033721, AMD (completed),
  phase I: NCT01271270, AMD (completed).
        
LHA510wet AMDLHA510: VEGFR-2 inhibitor
  phase II (completed, NCT02355028)(68)
        
PAN-90806AMDPAN-90806: VEGFR-2 inhibitor
  phase I (completed, NCT02022540)
  phase I/II (completed, NCT03479372)(68)
        
Sunitinibwet AMDSunitinib: blocks VEGF, by inhibiting its receptor(69)
  GB-102 (pan-VEGF receptor inhibitor) is a IVT injectable depot formulation of sunitinib malate(70)
  phase II (recruiting) NCT03953079(68)
  phase IIb study of GB-102 anticipated to begin enrollment in 2019(70)
  X-82 is a derived from sunitinib and is delivered orally(71)
  X-82 in phase II trial (APEX study) is in progress(72)
        
OTX-TKIAMDOTX-TKI: TKI implant
  phase 1 (recruiting, NCT03630315)(68)
        
TG100801AMDTG100801: phase 1 (completed, NCT00414999)
        
Regorafenibneovascular AMDRegorafenib: inhibits VEGFR receptor 2/3
  phase II (completed)(73)
        
PazopanibAMDPazopanib (multitargeted TKI of VEGFR)
  phase II [NCT01362348: macular degeneration (terminated)]
  phase II [NCT01134055: macular degeneration (completed)]
        
PTK787wet AMDPTK787 (TKI of VEGFR)
  phase I: NCT00138632 (completed)
        
AL-39324wet AMDAL-39324: multitargeted TKI of VEGFR
  phase II: NCT00992563 (completed)
Anti-VEGF Agents
Brolucizumabwet AMDBrolucizumab: a humanized antibody fragment (single chain) inhibitor, FDA approved(69,14)
        
Abiciparwet AMDAbicipar: an antagonist of VEGF-A
  phase III clinical trials undergoing in partnership with Allergan(74) (NCT02462486)
        
OPT-302wet AMDOPT-302: a fusion protein targeting VEGF-C and VEGF-D is being developed by Opthea(75)
  phase II trials, injected in combination with a traditional VEGF inhibitor(69)
        
RC28-EAMDRC28-E: a VEGF/bFGF dual decoy receptor (IgG1 Fc-fusion protein)
  phase 1 (recruiting, NCT03777254)(68)
        
KSI-301AMDKSI-301: phase 2 (recruiting, NCT04049266)(68)
        
IBI302neovascular AMDIBI302: a novel recombinant fully human bispecific fusion protein
  phase 1 (recruiting, NCT03814291)(68)
          
   
   
TAB014AMDTAB014: monoclonal antibody, inhibitor of VEGF
  phase 1 (recruiting, NCT03675880)(68)
        
Fovista (E10030)wet AMDa pegylated platelet-derived growth factor (PDGF) antagonist
  phase IIb clinical trial demonstrated the favorable trends attained with the combination (Fovista and Lucentis) in comparison to anti-VEGF monotherapy.(76,77)
  two phase 3 pivotal trials evaluating the benefits of combination therapy (Fovista and Lucentis) did not demonstrate any favorable trends as indicated by the mean change in visual acuity.
  the phase 3 clinical study assessing the superiority of combination therapy Eylea or with Avastin also did not yield conclusive benefits.(78,69)
 
Angiopoietin Pathway Inhibitors
 
RG7716 and REGN 910-3wet AMDhuman IgG1 monoclonal antibodies(79,80)
  both in phase 2 clinical trials (NCT01941082, NCT01997164)
 
Complement Pathway Inhibitors
 
ALXN-1102AMDrecombinant human fusion protein (anticomplement)
  is in preclinical testing in AMD(81)
        
POT-4 (AL-78898A)wet AMD, advanced neovascular lesionsis a synthetic peptide (complement C3 inhibitor)(82)
  phase I NCT00473928 (completed)
        
EculizumabGAmonoclonal antibody against complement component 5 (IV)(83)
  phase II: NCT00935883 (completed)
        
ARC1905 (Zimura)dry AMD, neovascular AMDaptamer that targets complement factor C5(69)
  administered by intravitreal injection
  phase I study has been completed (November 2012) but result have not been yet published.(84)
  Zimura (avacincaptad pegol), complement factor C5 inhibitor(69)
  Zimura phase IIa Safety Trialin Combination with Lucentis (results announced)(69)
        
APL-2dry as well as wet AMDAPL2: a PEGylated cyclic peptide complement C3 inhibitor being injected with anti-VEGF drugs
  presently undergoing evaluation in combination with anti VEGF drugs (phase II trial)
  significantly inhibited expansion of the area of atrophy (in phase II trials), advanced to phase III clinical trials(69)
        
Lampalizumab (FCFD4514S)GAan antigen-binding fragment of a humanized monoclonal antibody
  selective complement factor D inhibitor(85)
  two phase III trials targeting the complement factor D failed.
  phase II trial conducted by Apellis for evaluation of Lampalizumab as complement C3 inhibitor demonstrated optimistic results.(69)
        
LFG 316GAC5 inhibitor (intravitreal administration)(86)
 dry AMDphase II NCT01527500 (completed)
        
TA 106dry AMDanticomplement factor B(87)
  under preclinical investigation
 
Visual Cycle Inhibitors
 
FenretinideGAvisual cycle inhibitor (synthetic retinoid derivative)(24)
  phase II NCT00429936 (completed)
        
ACU-4429 (Emixustat)visual cycle inhibitor (nonretinoid) for geographic atrophyorally administered visual cycle modulator(4,88)
  phase II NCT01002950 (completed)
  phase II/III NCT01802866 (ongoing)
        
ALK-001visual cycle modulatorit is a modified vitamin A molecule that slows lipofuscin formation.
  phase I study for safety and pharmacokinetics studies were conducted (phase I, oral administration), however, the results are not posted yet.(89,90)
        
A1120AMD-like phenotypes in mouse modelsnon-retinol based antagonists of RBP-4
  accumulation of lipofuscin bisretinoids is decreased via chronic administration of A1120.(91)
 
α5β1integrin Inhibitors
 
JSM6427CNVselective inhibitor of integrin 51(92)
  phase I: NCT00536016 (completed).
        
VolociximabAMDa chimeric monoclonal IgG4 antibody that binds α5β1integrin(93)
  phase I (NCT00782093 (completed, AMD)
 
Others
 
iSONEP (sonepcizumab)wet AMDa humanized monoclonal antibody targeting sphingosine 1-phosphate
  in phase II (wet AMD)(94)
        
Fosbretabulin (CA-4P)CNVvascular disrupting agent
  its active metabolite inhibits the microtubule assembly.(95)
  phase II: NCT01423149 (completed)
        
Oraceadry AMDantibiotic (doxycycline)(69)
  promotes photoreceptor survival(96) and is in phase II/III clinical trials (NCT01782989)
        
Dorzolamide-Timololwet AMDDorzolamide-Timolol (Cosopt) eye drops used for glaucoma
  Dorzolamide-Timolol in combination with anti-VEGF drugs for wet AMD (in phase III trials, NCT03034772)(69)
        
Trimetazidinewet AMDanti-ischemic agent with cytoprotective effects (oral)(97)
  phase III ISRCTN99532788 (completed, not published)
        
MC-1101dry AMDa small-molecule topical eye drops(98)
  increased choroidal blood flow (topical)
  phase II/III NCT02127463 (ongoing)
        
NT-501 (CNTF)GAan implanted encapsulated cell technology
  a ciliary neurotrophic factor, a neuroprotective cytokine that prevents photoreceptor(99)
  phase II NCT00447954 (completed)
        
Brimonidine tartrateGAα2 adrenergic receptor agonist
  exerts neuroprotective effects(100)
  phase II NCT00658619 (completed)
        
GSK 933776GAhumanized monoclonal antibody against amyloid beta given as intravenous infusion into the blood(101)
  phase II NCT01342926 (ongoing)
        
SF0166AMDsmall-molecule αvβ3 antagonist
  phase I/II (completed, NCT02914639)(68)
        
AKST4290refractory neovascular AMDorally administered CCR3 inhibitor
  phase IIa (completed)(102)
        
CLG561GAproperdin inhibitor
  phase II (NCT02515942)(68)
        
IONIS-FB-LRxmacular degenerationgeneration 2+ ligand-conjugated antisense (LICA) drug
 geographic atrophyphase II (recruiting, NCT03815825)(68)
        
ASP7317AMDinvestigational therapy derived from pluripotent human stem cells
  phase I/II (recruiting, NCT03178149)(68)
        
HB002.1MAMDhuman immunoglobulin Fc fusion protein
  phase I (recruiting NCT03387566)(68)
        
TK001 (sevacizumab)neovascular AMDrecombinant humanized monoclonal antibody
  phase I (recruiting NCT03021785)(68)
        
RO7171009AMDintravitreal injection (investigational drug)
  phase II (recruiting, NCT03972709)(68)
        
BI 754132AMDphase I (recruiting) NCT04002310(68)

2.2. Glaucoma

Glaucoma is irreversible neurodegeneration that involves retinal nerve fiber layer thinning, optic nerve head cupping, and retinal ganglion cell (RGC) death.(103) Essentially, glaucoma damages the optic nerve of the eye, which usually occurs after a buildup of fluid that leads to increased intraocular pressure (IOP).(103) Primary open glaucoma and angle-closure glaucoma are the two major subtypes of glaucoma. The categorization was made on the basis of the opening and closing of the iridocorneal angle (Figure 4). The former usually occurs when the eye is unable to properly drain and includes glaucoma symptoms that cannot be attributed to other diseases, injuries, or a closed iridocorneal angle.(104) Primary open glaucoma is painless, does not cause any change in vision initially, and is asymptomatic during its early stages.(103) Angle-closure glaucoma occurs when the iris is very close to drainage angle and comes in physical contact with the trabecular meshwork (TM) in the eye, which leads to its blockage. The eye pressure rapidly increases when the drainage angle is completely blocked, which is considered an acute attack.(103−105) Normal-tension glaucoma (NTG) is a form of open-angle glaucoma (OAG) that involves optic nerve damage in patients with IOP < 21 mmHg (normal range 12–22 mmHg).(105,106) Secondary glaucoma is a form that encompasses many types of glaucoma with the identifiable cause of increased IOP, which leads to optic nerve damage.(107) The most important risk factor for chronic OAG is elevated IOP (>21 mmHg). As such, the contributing factors for the progression of glaucoma are presently not fully characterized;(4) however, RGC death is a crucial element in the pathophysiology of glaucoma (all forms), and delaying or halting RGC loss is considered to be a potential strategy to preserve vision in glaucoma. The molecular basis of RGC death has been significantly explored which indicates that a variety of molecular signals are involved, including axonal transport failure, mitochondrial dysfunction, oxidative stress, excitotoxic damage, deprivation of neurotrophic factor, synaptic connectivity loss, and others.(108)

Figure 4

Figure 4. Conventional pathway for aqueous humor.

Although IOP is the readily monitored causal risk factor, a reduction in IOP does not ensure the cessation of disease progression. Moreover, elevated IOP is not necessarily responsible for RGC death and vision loss in NTG. Nevertheless, the principal proven method of treatment is IOP reduction based on the use of topical drugs, laser therapy, and surgical intervention.(109,110) In general, drugs cause IOP reduction via three mechanisms: (a) decreasing the aqueous production in ciliary body, (b) increasing the aqueous humor (AH) outflow through the TM, and (c) increasing the AH outflow via the uveoscleral pathway.(110) Eye drops and the systemic application of glaucoma medications are employed for the reduction of IOP. In addition, combinations of glaucoma medications are also (Table 3).(105,111) In the cases where these therapeutic modalities fail, surgical procedures are used to maintain an adequate humor outflow. Surgical techniques such as argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT) increase outflow by damaging TM tissue. The increase in the AH outflow is assumed to be caused either by an increase in macrophages or the scarring of the TM.(112) A glaucoma laser trial (GLT) conducted two decades ago drew attention to laser trabeculoplasty and demonstrated reduced IOP in eyes treated with ALT along with better visual field in comparison to eyes treated with topical medication. Later, SLT was introduced, which superseded ALT, as it caused lesser damage to the TM architecture. In general, SLT is considered to be a safe alternative for IOP reduction, as the treatment outcomes have reported fewer adverse events as well as better repeatability.(113) However, the lowering of IOP with SLT to clinically acceptable levels might require the use of additional medication.(112) Recently, the “LIGHT” study, a multicenter randomized trial conducted in the United Kingdom (laser-first, n = 356, or medicine-first, n = 362), supported the use of SLT for the treatment of ocular hypertension (OHTN) and OAG. The study outcome demonstrated the progression of glaucoma in a lower proportion of patients in the laser arm first in comparison to the medicine arm first.(114) Another option, trabeculectomy, involves the removal of a part of the eye’s TM and adjacent structures to relieve the IOP by increasing the outflow; this surgery is sometimes followed by the addition of a shunt to maintain the opening created by surgery. A shunt implant might attenuate the complications associated with trabeculectomy.(115) Laser peripheral iridotomy is another procedure that employs a laser device to create a hole in the iris that allows the AH outflow despite the closed iridocorneal angle.(116)
Table 3. Management of Glaucoma
ClassExampleIOP reduction mechanismFDA approved medications(117,111)
prostaglandinsLatanoprostrelaxes the muscles in eye’s interior structure that leads to better outflow of fluidsXalatan (Pfizer), Rescula (Novartis), Travatan Z (Alcon), and Lumigan (Allergan)
 Bimatoprost  
 Travoprost  
        
beta-blockersTimololdecrease the AH production in the eyeTimoptic XE (Merck), Betoptic S (Alcon). and Istalol (ISTA)
 Betaxolol  
        
alpha-adrenergic agonistsBrimonidinedecrease the rate of AH production.Iopidine (Alcon), Alphagan (Allergan). and Alphagan-P (Allergan)
 Apraclonidineepinephrine exerts dual action: 
  (a) decreases the rate of AH production 
  (b) increases the AH outflow 
        
carbonic anhydrase inhibitorsDorzolamidedecreases the rate of AH productionTrusopt (Merck), Diamox (Sigma), Azopt (Alcon), and Daranide
 Acetazolamide  
 Methazolamide  
        
parasympathomimeticsPilocarpineincrease AH outflow from the eyeOcusert, Propine, Carbastat, Miostat, Phospholine iodide
 Carbachol  
        
combinations: glaucoma drugs used when combination of drugs is required to control IOP(1) commercial name: GanfortR
   drug 1: Bimatoprost 0.03%
   drug 2: Timolol 0.5%
   (2) commercial name: XalacomR
   drug 1: Latanoprost 0.005%
   drug 2: Timolol 0.5%
   (3) commercial name: DuotravR
   drug 1: Travoprost 0.004%
   drug 2: Timolol 0.5%
   (4) commercial name: CosoptR
   drug 1: Dorzolamide 2%
   drug 2: Timolol 0.5%
   (5) commercial name: AzargaR
   drug 1: Brinzolamide 1%
   drug 2: Timolol 0.5%
   (6) commercial name: CombiganR
   drug 1: Brimonidine 0.2%
   drug 2: Timolol 0.5%
   (7) commercial name: Simbrinza
   drug 1: Brinzolamide
   drug 2: 1% Brimonidine 0.2%
As such, eye drops are preferred over surgery and are quite effective in controlling IOP.(111) Both medication and surgery can halt the further loss of vision; however, vision loss cannot be regained, and glaucoma is not curable.(105)
It is important to mention that despite the treatment, approximately 15–20% of glaucoma patients eventually become blind in at least one eye.(118−120) However, there is a variability in blindness rates between the reports made on the basis of observations from the real world and clinical investigations (clinical trials), as evidenced by the higher progressive visual field loss in the real world. The reason for this difference could be the fact that patients who are participants in longitudinal studies are more attentive toward the disease and receive frequent examinations as well as better evaluations.(121) This is evident from the results of a study conducted in 2010 (last visit before the death of the patients), demonstrating that 42% of the treated eyes were unilaterally blind, whereas bilateral blindness was observed in 16.4%.(122)

2.2.1. Targets/Chemical Classes

2.2.1.1. ROCK Inhibitors
ROCK, a serine/threonine protein kinase, is activated via interaction with a small GTP-binding protein. ROCK-I and ROCK-II are the two highly homologous isoforms that exhibit absolute identity in their ATP-binding site.(123) Rho-ROCK signaling regulates cellular adhesion, proliferation, motility, differentiation, and apoptosis.(124) ROCK inhibitors exert a direct effect on the conventional AH outflow pathway (Figure 5). In addition, these inhibitors also hold significant promise for the treatment of glaucoma owing to their capacity to increase retinal blood flow and induce neuronal protection against stress.(124) The structures of several ROCK inhibitors are shown in Figure 6. The details of the FDA-approved Netarsudil and clinical trial results of other ROCK inhibitors are presented in the following section (Netarsudil (Rhopressa, AR-13324)) and Tables 4 and 5).

Figure 5

Figure 5. Rock and LIM kinase inhibition.(109) Adapted with permission from ref (109). Copyright 2016 American Chemical Society.

Figure 6

Figure 6. ROCK inhibitors.(124−134)

Table 4. Clinical Trial Study Results of Netarsudil
Study designResults
double-masked, randomized, dose–response studyDemonstrated statistically significant IOP reductions (0.01% and 0.02%)
 A comparative analysis with latanprost indicated that AR-13324 0.02% was slightly less effective.
 Ocular hyperemia was observed with both the concentrations of AR-13324 in comparison to latanoprost.(142)
         
phase 3 (ROCKET-1 and ROCKET-2)Two randomized, double-masked trials were conducted.
 Netarsudil (0.02%, qd) was found to be noninferior to timolol (0.5%) in subjects with baseline IOP < 25 mmHg.
 Frequent adverse event was conjunctival hyperemia.
 Overall, netarsudil (0.02%, qd) was effective and well tolerated.(143)
        
phase 3 (ROCKET-3 and ROCKET-4 study)In majority of patients, mild conjunctival hyperemia was observed which was not found to increase after continued use over 3 months.(144)
        
phase 2 trialsCombination of netarsudil 0.02% and latanoprost 0.005% demonstrated superior ocular hypotensive efficacy in comparison to individual active components administered individually.
 Mild transient asymptomatic conjunctival hyperaemia was observed.(145)
        
Mercury1 and Mercury 2 trialsRoclatan demonstrated higher efficacy than latanoprost (0.005%) by 1.5–2.4 mmHg and netarsudil 0.02% by2.2–3.3 mmHg across all time points.
 Mild conjunctival hyperemia was observed.(146)
Table 5. Clinical Trial Study Results of SNJ-1656, AR-12286, and Ripasudil
Rho kinase inhibitorClinical update
SNJ-1656 (Y-39983)Developer: Senju Pharmaceutical Co.
 SNJ-1656 administered topically caused significant reductions in outflow resistance and IOP.(147)
 The efficacy and safety (topical administration, ophthalmic soloution, 0.003–0.1%) was assessed in a phase 1 clinical study. The results demonstrated that peak IOP reduction (3.0 ± 1.2 mmHg) was attained with 0.1% concentration at 4 h after instillation.(148)
 A placebo-controlled phase 2 clinical study evaluated multiple concentrations of the SNJ-1656 for 7 days in patients with primary OAG and OHTN. Significant IOP reduction was achieved with SNJ-1656 at 2 h following administration of the morning dose.(149)
        
AR-12286Developer: Aerie Pharmaceuticals
 A double-masked crossover study demonstrated clinically significant IOP reductions in normotensive subjects.(150)
 AR-12286 (0.25%) displayed a maximum average pressure reduction of approximately 4.5 mmHg in comparison to placebo in a randomized phase 2 clinical trial.(151)
 This rock inhibitor was later abandoned by Aerie Pharmaceuticals mainly due to frequently encountered conjuctival hyperemia in 60% patients.(152)
        
RipasudilDeveloper: Kowa Company
 First Rho kinase inhibitor to be approved (Japan, September 2014)(153)
 A 0.4% BID dose was established as a clinically useful concentration of ripasudil and dosing frequency in phase 1 and phase 2 clinical trials.(154)
 A phase 2 randomized clinical study demonstrated significant dose dependent reduction from baseline IOP (23.0–23.4 mmHg) to −1.9, −3.2, – 2.7, and −3.1 mmHg with placebo (0.1, 0.2, and 0.4% concentrations) at 8 h after instillation. Overall 0.4% ripasudil was established as the optimal dose.(155)
 The results of parallel group comparison studies revealed additive IOP-lowering effects found at peak (1.6 mmH) and trough (0.9 mmHg) with the combination of ripasudil-timolol and (1.4 mmHg) at peak level with ripasudil-latanoprost.(156)
 A multicenter, prospective, open-label study (0.4% ripasudil, twice daily for 52 weeks) showed IOP reductions at trough and peak of −2.6 and −3.7 mmHg in patients with POAG or OHTN.(157)
 Ripasudil 0.4% induced conjunctival hyperemia with peak intensity at 15 min that resolved over 120 min.(158)
 A clinical investigation involving ripasudil addition to existing treatment regimens demonstrated favorable trends both in terms of safety as well as effectiveness in lowering the IOP. Significant lowering in IOP was seen in patients after 1 month (17.5 ± 4.5 mmHg) and 3 months (16.8 ± 4.2 mmHg) of treatment.(159)
 Several other studies reported IOP reductions from baseline on treatment (adjunctive) with ripasudil in Japanese patients that were already receiving medical therapy.(160)
 Another clinical study established the use of ripasudil as an adjunctive therapy to attain IOP reductions in patients that did not satisfactory response to other maximal tolerated medical therapies.(161)
 It was found to reduce the aqueous flare in anterior hypertensive eyes.(162)
 Another study revealed the potential of ripasudil to decrease IOP in inflammation- and corticosteroid-induced OHTN.(163)
 Ripasudil demonstrated neuroprotective effects and delayed RGC death via suppression of reactive oxygen species on oral administration.(164)
Netarsudil (Rhopressa, AR-13324). Netarsudil, developed by Aerie Pharmaceuticals, is a Rho kinase and norepinephrine transporter inhibitor. Chemically, it belongs to class of amino-isoquinoline amides.(7,135,136) It was approved as a 0.02% formulation in the USA in 2017. Its IOP-lowering potential is attributed to its dual mechanism of action that leads to increased outflow facility and decreased AH production as well episcleral venous pressure.(10,137−139) The US FDA recently approved the FDC of latanoprost (0.005%) and netarsudil (0.02%) as Roclatan for OAG and OHTN. The success of this FDC is attributed to the IOP-lowering activity of netarsudil, which complements the latanoprost-mediated increased uveoscleral outflow.(10)
Netarsudil demonstrates good penetration through the cornea, as its highest concentration is found in the cornea followed by the conjunctiva. Corneal esterase converts netrasudil to netarsudil M1, the metabolically active form (Figure 7).(10,140) In a preclinical study, the corneal metabolism of netrasudil was evaluated, and the results revealed rapid metabolism of netarsudil in dogs (t1/2 = 98 min). Corneal metabolism studies were also conducted in monkey, rabbit, pig, and human corneal tissue, and netarsudil demonstrated t1/2 values of 109, 140, 156, and 175 min, respectively. Investigations on the ocular metabolism of netarsudil revealed the detection of Netarsudil-M1 (AR-13503) in all the AH samples, whereas concentrations of netarsudil were found to be below the limit of detection. Netarsudil-M1 was found to be endowed with five times higher inhibitory potency toward ROCK1 and ROCK2 than the parent drug (Ki of 0.2 nM for each ROCK isoform). The metabolite also caused higher disruptions of actin stress fibers and focal adhesions than netarsudil.(140) Another recent study investigated the effects of netarsudil-M1 in enucleated human eyes, and the results indicated that the metabolite significantly increased the outflow facility in human eyes.(141) Overall, the revelations ascertain the potential of netarsudil-M1 (AR-13503) as a potent ROCK inhibitor. A phase 1 study evaluating an AR-13503 implant alone and in combination with aflibercept has already been initiated (NCT03835884).

Figure 7

Figure 7. Netarsudil as prodrug.

2.2.1.2. Adenosine Receptor Ligands
It has been well reported that the adenosine system is a potential target for the development of therapeutics for glaucoma. Adenosine is a ubiquitous local modulator that stimulates four membrane receptors, namely, A1, A2A, A2B, and A3, and regulates various physiological and pathological functions. Adenosine receptors (ARs, family: G protein-coupled receptors) regulate the adenylyl cyclase, thereby affecting the production of cAMP, which is important in the regulation of AH dynamics in ocular tissues as well as cell death and growth in the retina and optic nerve (Figure 8).(109,165) An update on AR agonists in clinical trials is presented in Table 6.

Figure 8

Figure 8. Signaling cascade for AR agonist and antagonist.(109) Adapted with permission from ref (109). Copyright 2016 American Chemical Society.

Table 6. AR Agonists in Clinical Trials(166−169)
2.2.1.3. Nitric Oxide (NO) Derivatives of Prostaglandins and Other Related Compounds
NO is an endogenous messenger produced under the action of nitric oxide synthase (NOS).(170,171) NO mediates IOP maintenance and controls basal ocular vascular tone via sGC signaling pathway activation.(172,173) Owing to this, a hybrid drug design strategy has been utilized to design scaffolds via fusion of antiglaucoma scaffolds with NO-donor moieties. The hybrid drug design in this context has been extensively employed to design NO-donating derivative of prostaglandin (PGF2α) analogues that are most frequently used for the lowering of IOP. Such hybrid scaffolds induce significant reduction in IOP via concomitant activation of two independent mechanisms: prostaglandin F (FP) receptor activation and sGC/cGMP stimulation in target tissues. NO-induced enhanced vasodilatation, antiplatelet activity, and anti-inflammatory effects are considered to be instrumental in the success of this class of drugs.(174) Other than the NO-donating derivative of prostaglandin (PGF2α) analogues, research has also been initiated toward the development of an NO-donating derivative of the phosphodiesterase-5 (PDE5) inhibitor as a future generation NO donors.(175) This section will discuss the updates on the FDA approved NO-donating PGF2α analogue as well as the hybrid scaffolds undergoing clinical and preclinical investigations.
Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%, lbn). LBN is the most advanced example of an NO-donating PGF2α analogue (Figure 9) that exemplifies the success of this hybrid drug design strategy. Initially discovered by Nicox and later licensed by Bausch + Lomb, the ophthalmic solution received FDA approval in November 2017 for the lowering of IOP in patients with OAG and OHTN. This antiglaucoma medication is one of the first new glaucoma drops to hit the market in 20 years with a dual-action approach.(8,176,177) LBN undergoes rapid metabolism in situ by esterases and releases latanoprost acid and butanediol mononitrate, which further metabolizes to 1,4-butanediol and NO, leading to simultaneous activation of FP receptors and the NO/soluble GC/cGMP signaling pathway. This increases both uveoscleral and conventional outflow, causing significant lowering of the IOP.(172,8,176−181) Initial preclinical studies by Krauss et al. revealed that LBN demonstrated effective control of IOP in laser-induced OHTN cynomolgous monkeys and blunted the hypertensive response to intravitreal injection of hypertonic saline in a rabbit model of transient OHTN along with a rapid decrease in IOP. LBN also exerted potent stimulation of the sGC signaling pathway in PC12 cells and in human HEK293 cells. Collectively, the results indicated that LBN possessed higher IOP-lowering activity than latanoprost, possibly due to the concomitant contribution of NO and latanoprost acid.(181) The results were further supported by the favorable outcome of the several clinical studies that demonstrated a higher IOP-lowering potential of LBN than latanoprost (Table 7).

Figure 9

Figure 9. LBN and NO derivatives of prostaglandins.

Table 7. Clinical Update of LBN
Clinical Trial no.Study DesignResultsConclusion
(1) NCT01895985 (Kronus, phase I)study type: single-center, controlled, open-labelmean change in IOP (mmHg): 3.6 ± 0.8 (treated eye), 3.5 ± 0.9 (fellow eye)LBN significantly lowered mean IOP during the entire 24 h period.(182)
 subjects: healthy japanese subject (n = 24)  
 duration: 14 days  
 ARMS: LBN  
 dosage: 0.024% qPM  
          
(2) (NCT01223378) (Voyager, phase II)study type: multicenter, randomized, controlled, investigator masked, dose-rangingmean change in IOP (mmHg): 0.024% qPM 8.3, day 7; 8.9, day 14; 9.0, day 28LBN 0.024% exerted significantly higher IOP reductions than that of latanoprost 0.005%.(183)
 subject: 413  
 duration: 28 days  
 ARMS: LBN, LTN  
 dosage: 0.006, 0.012, 0.024, 0.040 0.024% (LBN, qPM); 0.005% (LAT, qPM)  
           
(3) NCT1707381 (Constellation, phase II)study type: single-center, randomized, controlled, open-label, crossovermean change in IOP (mmHg): 1.1–1.2, diurnal/wake, 2.3 ± 3.0, nocturnal/sleepLBN exerted higher IOP reduction than timolol during the nocturnal period.(184)
 subject: 25  
 duration: 8 weeks, crossover at 4 weeks  
 ARMS: LBN, TIM  
 dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM)  
         
(4) NCT01749904study type: multicenter, double-maskedmean change in IOP (mmHg): 1.2, 1.4, and 1.1, week 2; 1.0, 1.3, and 1.3, week 6; 1.0, 1.3, and 1.3, 3 monthsLBN exerted higher IOP lowering effects than timolol 0.5%.
 subject: 420 LBN was safe as well as effective in these subjects with OAG or OHTN.(185)
 duration: 3 months  
 ARMS: LBN, TIM  
 dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM)  
        
(5) NCT01749930 (Lunar, phase III)study type: multicenter, randomized, controlled, double-maskedmean change in IOP (mmHg): 0.4, 0.8 and 0.7, week 2; 0.9, 0.8, and 1.0, week 6; 0.9, 1.3, and 1.3, 3 monthsLBN 0.024% QD in the evening was found to be noninferior to timolol 0.5% BID.
 subject: 420 displayed significantly greater IOP lowering potential in subjects with OAG or OHTN
 duration: 3 months LBN was found to be safe and effective.(186)
 ARMS: LBN, TIM  
 dosage: 0.024% (LBN, qPM), 0.5% (BID, qPM)  
          
(6) NCT01895972 (Jupiter, phase III)study type: multicenter, open labelmean change in IOP (mmHg): 4.3, 4 weeks; 5.3, 1 yearLBN resulted in significant and sustained IOP reduction.(187)
 subject: 130 (Japanese subjects)  
 duration: 1 year  
 ARMS: LBN  
 dosage: 0.024% (LBN, qPM)  
          
(7) NCT03931317study type: randomized, single center, masked, crossover study Study aim: comparative evaluation of LBN and TIM on retinal blood vessel density and visual acuity.
 subject: 40 Status: recruiting
 duration: 8-week  
 ARMS: LBN, TIM  
 dosage: 0.024% (LBN, qPM), 0.5% BID  
         
(8) NCT03949244 (phase 4)Study type: randomized, interventional study Study aim: to evaluate the effect of Nailfold Application of LBN on Nailfold capillary blood flow.
 Subject: 60 (estimated) status: not yet recruiting
 ARMS: LBN, LTN  
 Dosage: 0.024% (LBN), 0.5% (LTN)  
Other NO-donating PGF2α analogues and future generation NO donors. In 2010, Borghi et al. designed NCX-125 (Figure 9), an NO-donating latanoprost analogue. The dual-action compound was synthesized employing EDC-mediated amide coupling between 2-hydroxypropane-1,3-diyl dinitrate and latanoprost-free acid. NCX-125 demonstrated significantly higher IOP-lowering potential in rabbit, dog, and nonhuman primate models compared with latanoprost. It induced NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. In addition, anti-inflammatory activity was also exhibited by NCX-125, indicating its therapeutic usefulness in glaucoma.(188)
Studies were also conducted on NCX-139 (Figure 9), another analogue composed of latanoprost amide and an NO-donating moiety. The outcome of the study demonstrated the remarkable IOP-lowering activity of NCX-139 in glaucomatous dogs as well as OHTN rabbits. Moreover, an NO-mediated vascular relaxant effect was displayed by NCX-139, along with the displacement of 3H-PGF2α binding on recombinant human FP receptors. Overall, NCX 139 exhibited dual action: NO/cGMP signaling and FP receptor. A comparative analysis of NCX-139 with its des-nitro analogue indicated that the respective des-nitro analogue was not effective at a therapeutically relevant dose.(189)
NCX 470, a NO-donating bimatoprost analogue (Figure 9), is presently in clinical development by NICOX. The chemical architecture of NCX-470 consists of an esterified hydroxyl group (15 position) with an NO-donating moiety [6-(nitrooxy) hexanoic acid].(175,190) In preclinical studies, NCX-470 demonstrated IOP-lowering activity in transient OHTN rabbits and exerted a more significant reduction in IOP (NCX 470, 0.042%) than bimatoprost (0.03%) in ocular normotensive (ONT) dogs and in laser-induced OHTN nonhuman primates.(191) Overall, NCX-470 has demonstrated greater IOP reduction (up to 3.5 mmHg) than bimatoprost in head-to-head comparisons, as evidenced by the results of nonclinical pharmacological studies conducted in animal models of glaucoma and OHTN.(175) These preclinical studies revealed that NCX 470 exerts its IOP-lowering action by activating the PGF2α and NO/cGMP signaling pathways. The findings are quite optimistic and have subsequently led to the initiation of phase 2 studies of NCX 470 in August 2018. Recently, Nicox announced the completion of enrollment in the phase 2 study of NCX-470. The study aims to determine the appropriate dose of NCX 470 for advancement to phase 3 studies.(192)
NCX 667, a novel NO-donor, was evaluated in three models of OHTN and glaucoma. Topical dosing of NCX 667 (1%) demonstrated significant lowering of the IOP and was found to be effective in the OHTN eyes of nonhuman primates.(193)
Recently, NCX-1741, a novel NO-donating derivative of avanafil (PDE5 inhibitor), demonstrated efficacy in lowering the IOP in ONT-rabbits and OHTN-monkeys. The results revealed that avanafil was found in the AH of ONT-rabbits following the ocular dosing of NCX-1741, and the IOP-lowering effects of NCX 1741 appeared to last up to 24 h.(194)
The new research programs of NICOX include investigations on NO-donating PDE5 inhibitors and NO-donating sGC stimulators as the future generation NO donors. The research program on these NO donors is influenced by the fact that the effect of NO in the sGC signaling cascade can be enhanced in the presence of sGC stimulators or PDE5 inhibitors.(192)
2.2.1.4. LIM Kinases
LIMK1 and LIMK2 are downstream from ROCK in the pathway that regulates the polymerization of actin filaments (Figure 5). LIMK inhibition in the TM promotes the depolymerization of actin filaments, which leads to the relaxation of the tissue, an increased outflow capability and a reduction in IOP. Thus, in addition to ROCK inhibitors, investigation of the downstream effects of LIMK inhibitors has opened an avenue for the development of promising IOP-lowering targets, such as MLC kinases and LIM kinases, which have presented optimism, as they are associated with lower side-effects due to their downstream location in the signaling pathway.(109,195) The representative structures of LIM kinase inhibitors are presented in Figure 10.(196,197)

Figure 10

Figure 10. LIM kinase inhibitors and EP2 receptor agonists

2.2.1.5. Nonprostanoid EP2 Receptor Agonists
Prostaglandin E2 induces several biological responses mediated by the signaling of EP receptor subtypes. Latanoprost and its active acid forms are selective FP receptor (prostaglandin F2α receptor) agonists that are considered to be quite effective IOP-lowering agents. However, the association of FP receptor agonists with some adverse effects has led to explorations revealing that the agonists of EP2 receptor in its free acid form are selective for the EP2 receptor and are effective in lowering IOP.(198) Subsequent efforts have led to the identification of the selective nonprostanoid EP2 receptor agonist omidenepag and its prodrug omidenepag isopropyl for the treatment of glaucoma.(199) The representative structures of EP2 Receptor agonists are presented in Figure 10.(198,199)

2.3. Diabetic Retinopathy (DR)

DR is the foremost common impediment of diabetes mellitus, leading to vision loss through damage to the retina. People between the ages of 25 and 74 who have had diabetes for 20 years or more have the highest possibility of developing DR.(200) Although there are no prior signals of DR, it can be diagnosed through the clinical observation of vascular deformities in the retina. The progression of DR can be broadly divided into two categories utilizing the occurrence of microvascular occlusions in the retina as a standard.(201) The first type is nonproliferative DR in which the vascular portion of the retina becomes more permeable and there is an increase in capillary lesions, and the second type is the proliferative DR, which can be distinguished by the neovascularization in the retina.(202) Generally, the major reason for the loss of vision in DR is the occurrence of a condition called diabetic macular edema (DME), which can occur in either of the two types of DR. The conditions may become more severe in DME through the decrease in the visual insight. During the course of DR, there is blood–retinal barrier breakdown due to diabetes, which is primarily responsible for DME, with subsequent leakage of vascular fluid into the sub- and intraretinal portions of the eye.(203) The release of this fluid and protein into the retina causes inflammation and thickening of the macula, which are considered to be the major characteristic features of DME.(204) The major cause of DR is hidden in its name, i.e., diabetes. The increase in blood sugar levels with time directs the obstruction of small blood vessels that help to nourish the retina, thus terminating its blood supply system. Consequently, new blood vessels grow by the efforts of the eye, but these vessels do not develop properly, are weak and leak into the neural retina, resulting in DR and other related pathologies.(204)
The pathological hypothesis of the progression of DR comprises the association of numerous extremely complex mechanisms that are linked to each other, thereby damaging the cellular portions of the retina. The pathology of DR involves different hypotheses based on the following three different pathological conditions.
(a)

Hyperglycemia and retinal microvasculopathy: microvascular damage is considered to be a major complication of DR whose pathology involves several metabolic pathways based on hyperglycemia.(205)

(b)

Inflammation: Another hypothesis for the pathogenesis of DR is based on inflammation. It is reported that at different stages of DR, chronic low-grade inflammation always occurs in diabetic animals and patients. Inflammation is responsible for leukostasis in the early stages of DR and causes the adherence of immune cells such as monocytes and granulocytes in the retinal microvasculature.(206)

(c)

Retinal neurodegeneration: It has been observed that degeneration of retinal neurons occurs through apoptosis in the early development period of DR in diabetic rats. It has also been reported that pro-apoptotic molecules are upregulated in diabetic animals and patients. In diabetic mice, apoptosis of mitochondria occurs, leading to their degeneration. The increase in glucose levels alsoleads to mitochondrial destruction in the retina. The degeneration of mitochondria is accompanied by a marked increase in reactive oxygen species, which constitute the oxidative stress to retinal neurons.(207)

2.3.1. Treatment for DR

Experts are presently focusing on the management of microvascular complications along with pharmacologically active molecules, laser photocoagulation therapy and vitreous surgery. The recently trending treatment strategy for both types of DR is the IVT administration of anti-VEGF agents, with the benefits of improving vision with fewer side-effects, while laser therapy helps to stabilize the vision (Table 8). Additionally, plasma kallikrein inhibitors have also displayed promising results for the treatment of DME (Table 9).
Table 8. Treatment for DR
TreatmentDetails
Intravitreal antiangiogenic agentsIVT therapies with anti-VEGF agents have displayed remarkable improvement. Administration of Ranibizumab (DRCR.net Protocol T, RESOLVE, and RESTORE trials), Pegaptanib (phase 2/3, multicenter, two-year trial), Aflibercept (VISTA, VIVID, DRCR.net Protocol T trials), and PDR (CLARITY trial) led to improvement of BCVA. Treatment with Bevacizumab (DRCR.net Protocol T trial) demonstrated reduction of retinal thickening.(208)
          
Intravitreal steroidsTriamcinolone (Off-label use): DEX implant (Ozurdex), FDA approved; FA insert (Iluvien, 0.2 mg), FDA approved(209)
            
Nonspecific antiangiogenic agents1. Squalamine (inhibits VEGF) phase 2 (withdrawn, NCT02349516)
 2. AKB-9778 (Tie2 activator) phase 2 (completed, NCT01702441)
 3. Nesvacumab (Tie2 activator) phase 2 (completed, NCT02712008)
 4. RO6867461 (inhibits VEGF and Tie2 activator) phase 2 (completed, N CT02699450)(210)
         
NSAIDS1. EBI-031 (IL-6 inhibitor) phase 1 (withdrawn, NCT02842541)
 2. Tocilizumab (IL-6 receptor antagonist) phase 2 (withdrawn, NCT02511067)
 3. Luminate (Inhibitor of integrin) phase 2 (completed, NCT02348918)(211)
             
Traditional laser phototherapy (adjunct in treatment of DME)1. Focal/grid laser: reduction in risk of vision loss and frequency of macular edema, improvement in visual insight.
 2. PRP: reduction in risk of visual loss and slows down the progress of retinopathy.(212)
          
New laser techniquesPASCAL: under developmental clinical phase (NCT03672656); accurate control of the laser with decreased treatment time.
 D-MPL: under developmental clinical phase (NCT03690050); minimum collateral damage.
 NAVILAS: phase 3 (completed, NCT02157350); high accuracy rate of laser spots.(213)
        
Retinal mitochondria specificMTP-131: (Ocuvia, cardiolipin inhibitor) phase 2 (completed, NCT02314299) ALA (mitochondria specific antioxidant) phase-3 (recruiting, NCT03702374).(214)
        
OthersLutein (antioxidant): phase-3 (completed, NCT00346333). Improvement in vision in DR patients.
 ARA290 (erythropoiesis initiator): phase-2 (ongoing, 2012-005486-13): reduction in neuroglial and vascular degeneration.
 Darapladib (L p-PLA2 inhibitor): phase-2 (completed, NCT01506895); remarkable improvements in BCVA and macular edema.(215)
Table 9. Plasma Kalkarien Inhibitors
InhibitorDetails
KV123833Developer: Kalvista pharmaceuticals
 On oral administration in mice, KV123833 was found to be significantly protective against retinal edema (VEGF-induced).
 VEGF injected intravitreally raised the retinal exposure of KV123833.(217)
        
KV998052 and KV998054Developer: Kalvista Pharmaceuticals
 Both are orally available plasma kalkarien inhibitors endowed with potential to avert and reduce VEGF induce edema.(219)
         
KVD001Developer: Kalvista Pharmaceuticals
 Most advanced small-molecule inhibitor
 Mode of administration: intravitreal
 Highest development stage: phase 2 (completed).
 Kalvista pharmaceuticals had collaborated with Merck in 2017 for the clinical progress of KVD001 after the drug cleared the phase 1 clinical studies along with other programs aimed at the development of orally administred plasma Kalkarien inhibitors.(220)
 The phase 2 clinical trial of KVD001 was conducted to evaluate its safety as well as efficacy in subjects that had earlier received therapy (anti-VEGF) but still had edema and reduced visual acuity. The outcome of the study failed to meet the primary end point (BCVA), however, favorable (protective) effects against vision loss were observed in study population (123 patients). The results of the study also indicated that KVD001 was well tolerated and safe.(216)
 After the completion of phase 2 studies of KVD001, merck decided to end the agreement with Kalvista pharmaceuticals on participation for further progress of KVD001 and related drugs.(221)
 Kalvista pharmaceutical is also conducting preclinical investigations on other plasma kallikarien inhibitors for oral administration and regulatory studies are ongoing in this context.(216)
         
THR-149Developer: Oxurion
 Bicyclic peptide-based plasma kallikarien inhibitor
 Mode of administration: intravitreal
 Highest development stage: phase 1 (completed, NCT03511898)
 Phase 1 studies were conducted to assess the efficacy of THR-149 to treat DME. The results of the investigation indicated favorable outcome in context of improvement of BCVA and no serious adverse events were observed.(222)
        
RZ402Developer: Rezolute Bio
 Small-molecule inhibitor of plasma kallikarien
 Mode of administration: oral
 Highest development stage: under preclinical investigation
 Suppression of retinal vascular leakage was demonstrated by RZ402 in studies conducted for macular edema in animal models.(223)
         
VE-3539Developer: Verseon Corp.
 Potent inhibitor of plasma kallikarien
 Mode of administration: oral
 Highest development stage: under preclinical investigation
 The compound has demonstrated favorable trends in the preclinical evaluation as evidenced the suppression of vascular leakage (retinal) and inhibition of retinal thickening.(224)

2.3.2. Plasma Kallikrein Inhibitors

Plasma kallikrein is an important target for treating DME, as the enzyme levels are increased in the vitreous fluid in patients with DME. Studies conducted in animal models revealed that the inhibition of plasma kallikrein reduced the retinal thickening and improved the processing of visual signals.(216) Some reports have also indicated the role of this enzyme in mediating VEGF-independent DME.(217) In light of the role of plasma kallikrein in DME and DR, small molecules as well as bicyclic peptide-based inhibitors are presently being explored to extract therapeutic benefits in these conditions.(218)

2.4. Dry Eye (DE)

DE syndrome affects the ocular surface of the eye due to a deficiency in adequate lubrication and moisture on the surface of the eye. Keratitis sicca, keratoconjunctivitis sicca, and dysfunctional tear syndrome are the other terms used to describe this disease. One of the DE symptoms is ocular-surface inflammation, which is a characteristic feature of DE detection.(225) Aqueous deficiency and evaporative DE represent the two main subtypes of the disease. Reduced aqueous (tears’ water component) production from the lacrimal glands leads to aqueous deficiency dry eye disease (DED), which is further categorized as Sjögren or non-Sjögren syndrome. The former occurs due to the infiltration of lacrimal and salivary glands by activated T-cells, while the latter occurs due to lacrimal gland insufficiency. Evaporative DE occurs due to lipid layer disorder, which leads to an increase in tear evaporation. Evaporative DE is the most common type of DED, accounting for approximately 85% of cases and is mainly caused by meibomian gland dysfunction.(226)

2.4.1. Treatments Currently in Use

Therapy for the treatment of DE is selected on the basis of the following parameters (Table 10).
Table 10. Treatments Currently in Use for Dry Eye
ParameterTherapy
quality and quantity of tears(I) DE with low aqueous content, three major strategies: (a) increasing the quantity of fluid on the ocular surface, (b) decreasing tear evaporation, (c) elevating the lipid content or lubricity of the tears.
 (2) For curing DE: topical lubricanting medications as drops, gels, and ointments
 for example: polymer hydroxypropyl guargellable lubricant eyedrops (Systane) by Alcon, diquafosol tetrasodium ophthalmic solution cyclooxygenase inhibitors, and resolvin analogues
 (3) Surgical approaches and laser trabeculoplasty are alternative available options for treating DE.(226)
         
inflammationInflammation, one of the signaling pathologies of DE, can be treated by currently available two topical medications: (1) Nonglucocorticoid immunomodulatory agent, 0.05% cyclosporine ophthalmic emulsion (Restasis, Allergan) that acts by increasing tear production. (2) 0.5% lifitegrast ophthalmic solution, approved by FDA in 2016, acts as antagonist of lymphocyte function-associated antigen 1 (LFA-1) (Xiidra, Shire) for the treatment of DED.(227)
         
lifestyle and dietary conditionsThis category involves a kind of management therapy for DE ensuing to sufficient intake of fluid, modest use of alcohol, employing humidifiers or protective eyewear, avoiding air conditioning and forced-air heating, and proper sleep.(228)
         
lid disease treatmentThe link of lid disease with DE is based on the fact that the malfunctioning of sebaceous glands, meibomian glands or glandulae tarsales, located in eyelids can also lead to dry eye as they are involved in secreting lipids that prevents the aqueous phase evaporation by forming a superficial tear film layer over eye. The treatment involves the topical application of antibacterial agents such as azithromycin or topical low-dose glucocorticoids, also combinations of the two agents can be used for short-term treatment, however, oral tetracyclines can be employed for longer periods.(229)
         
hormone therapyRecent studies stated that androgens can also be employed topically for treating DE but until now this therapy has not been recommended for treating DE clinically(230)
It is noteworthy to mention that both cyclosporine and lifitegrast as therapeutics for DED appear to be appropriate choices in cases where the satisfactory relief in symptoms cannot be achieved via artificial tears. In the future, clinical studies need to be conducted to establish a comparative safety and efficacy analysis of cyclosporine and lifitegrast and to evaluate the effects of these two drugs in combination.(231)

2.5. Cataracts

Cataracts are a slowly growing disease condition of the eye in which the lens becomes opaque, leading to cloudiness or a loss of transparency that may affect one or both eyes. As such, cataracts are commonly caused by aging or an injury to the eye’s lens,(232) while genetic disorders responsible for other health issues also increase the risk of cataracts.(233)
Depending upon the cause, cataracts are divided into the following categories: pediatric cataracts, age-related cataracts, and cataracts secondary to other causes. Oxidative stress is the key reason for the opaqueness of the lens. On the basis of the location of the opaqueness within the lens, cataracts (age-related) are further categorized into three subtypes: nuclear, posterior subcapsular, and cortical cataracts. The epithelial cells of the lens are extremely active (metabolically) and undergo oxidation, becoming insoluble with the cross-linking that occurs between them. These cross-linked epithelial cells then move toward the center of the lens, forming fibers that are compressed gradually, resulting in sclerosis of the lens and leading to opacity. Cortical cataracts are often wedge-shaped and similar to the spokes of a wheel that initiate from the cortex (outer part) and expand to the central portion of the lens, and posterior subcapsular cataracts are characterized by plaque-like opaque deposits in the rear of the lens.(234)
It is thought that only adults or elderly people are affected by cataracts, but this is not true, as children can also be confronted with this ailment. Pediatric cataracts mostly occur due to inherited traits that sometimes may be congenital or acquired, and this condition can occur unilaterally or bilaterally in more than one part of the lens with variations in size from tiny dots to dense clouds.

2.5.1. Treatment Strategies

Surgical removal of cataractous lens and its replacement with an intraocular lens (IOL) is an established method of treatment in case cataract becomes visually significant.(235,236) Over the years, there has been significant advancement in the field of surgical technology and techniques.(236) The surgery poses the benefit of correcting the refractive errors via accurate calculation of IOL power (biometry).(237,238) Although cataract surgery becomes essential when there is sufficient vision loss, it is seldom used to treat lens-induced inflammation, permit adequate retinal visualization, or thwart conditions such as glaucoma. As such, the result of cataract surgery does not depend upon preoperative visual sharpness. Three kinds of surgery are available: intracapsular cataract extraction, phacoemulsification, and extracapsular cataract extraction. Intracapsular cataract extraction involves lens removal and involves a high rate of complications owing to the large incision required. Opening of the lens capsule along with the removal of the nucleus and the cortex of the lens is involved in extracapsular cataract extraction, which is performed through a small incision.(239) The internal lens of the eye is emulsified with an ultrasonic handpiece in phacoemulsification and aspirated through a 2.2–3.2 mm incision. Phacoemulsification offers quick visual recovery and less postoperative inflammation and is considered to be the procedure of choice for surgical extraction.(240) Overall, phacoemulsification with implantation of a foldable IOL represents the common methodology utilized in cataract surgery and induces a relatively low stress level in patients under local anesthesia.(236,241) The last stage of treatment includes the implantation of the IOL after surgery.(242)
An IOL is commonly made of acrylic (foldable), poly(methyl methacrylate) (not foldable), or silicone (foldable).(236,243) The selection of the IOL is achieved through A-scan ultrasonography and keratometry. The results of these tests determine the approximate refractive power of the IOL required, depending on its location inside the eye: the posterior or anterior chamber. To calculate the correct IOL power, careful selection of formulas is of utmost importance. The Barrett Universal II formula and the Haigis-L method represent two extensively employed formulas to determine the IOL power.(236,243,244)
Various types of IOL are available for the replacement of the eye’s natural lens, such as (i) monofocal lenses that correct the spherical power; (ii) bifocal, trifocal, or multifocal IOLs to correct presbyopia, and (iii) toric IOLs to correct astigmatism.(236,243) Despite the fact that multifocal IOL results in better uncorrected vision,(245) the majority of the cataracts patients undergo monofocal IOL implantation owing to the relatively higher cost of astigmatism-correcting IOLs.(236)
The design of IOLs has undergone significant changes in the recent past, and specially designed aspheric IOLs(246) and blue-light-blocking IOLs(247) are available for attenuating ocular spherical aberration and blue-wavelength light, respectively.(236)
Lens-refilling surgery has also emerged as a potential therapeutic intervention for cataract, which involves the replacement of lens material with an injectable (bio)polymer capable of retaining the natural mechanical and optical lens properties.(248) Femtosecond laser-assisted cataract surgery is also a potential technology that employs the use of laser rendering automation for cataract surgery.(236,249)
Posterior capsule opacification is frequently treated with neodymium-doped yttrium aluminum garnet laser capsulotomy. Laser capsulotomy is employed to open a hole in the posterior capsule that allows improved clarity of the visual axis. Despite being safe and effective, it is associated with minor complications, including an increase in the IOP.(236,243,250)
Despite these significant advances in cataract surgery, there are several barriers/factors that prevent rural and remote communities from undergoing this treatment, such as cost of surgery,(251−253) lack of patient awareness, sociocultural belief that medical intervention is not required for blindness caused due to old age,(254,255) and shortage of ophthalmologists.(256) Other than the initiation of awareness programs and fabrication of subsidy schemes for cataract surgery for patients in rural areas, efforts must be adequately directed toward the development of small-molecule therapeutics that can be extremely helpful in expanding treatment in remote areas. In this context, Gestwicki et al. has significantly contributed in the recent past and reported a treatment approach to restore transparency in cataract models.(257) The study was based on the fact that damage to the major lens crystallin proteins leads to their misfolding and accumulation into insoluble amyloids, which causes cataracts. Capitalizing on this valuable information, the research group led by Gestwicki reported a sterol that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro using thermal stability studies. Initially, 2450 compounds of both natural and synthetic origin from the MS2000 and NCC collections were screened. Hsp27 was used as a model in view of its relatively high melting transition. A total of 45 compounds were identified by the primary screen that decreased the apparent Tm (±0.6 °C). Further explorations employing the R49C cryAA and R120G cryAB mouse models of hereditary cataract led to the identification of 5-cholesten-3β,25-diol (26, VP-101) as a potential agent that improved lens transparency. Reversal of cataract formation was also evidenced in vitro and in the R120G cryAB knock-in mouse. Moreover, partial restoration of protein solubility was also caused by the sterol in the lenses of aged mice in vivo and in human lenses ex vivo. Overall, it was concluded that the oxysterol 26 (VP-101) is a potential compound for the treatment (nonsurgical) of both hereditary as well as age-associated cataracts.(257) To further explore the binding mechanism of oxysterol 26 (VP1-001), its enantiomer (ent-VP1-001) was tested for its capacity to bind and stabilize cryAB in vitro and was also evaluated for its efficacy in cryAB(R120G) mutant and aged wild-type mice with cataracts. The experiments were specifically designed to ascertain the impact of stereoselective binding to cryAB on the activity. In the study, the binding of 26 (VP1-001) and 27 (ent-VP1-001) to cryAB was compared using in silico docking, microscale thermophoresis (MST), and DSF. The results of the docking study indicated a greater binding of 26 (VP1-001) into a deep groove in the cryAB dimer in comparison to 27 (ent-VP1-001). The binding of 26 (VP1-001) to cryAB was also evident from the DSF and MST experiments, whereas 27 (ent-VP1-001) did not bind to cryAB. The results also demonstrated a marked improvement in lens clarity, along with favorable morphological changes in lens with 26 (topical treatment), whereas 27 (ent-VP1-001) did not display any such effect. Collective results deduced that binding of 26 to native cryAB dimers is critical for its capacity to reverse the lens opacity (Figure 11).(258)

Figure 11

Figure 11. VP-101 as a promising compound that improved lens transparency.

Advancements have not just been made to improve the surgical procedures for cataract or in the development of small-molecule therapeutics; adequate efforts have also been invested to improve the outcomes in the postoperative phase. As a result, ReSure sealant, an ocular sealant (polyethylene glycol synthetic hydrogel), received FDA approval in 2014, as it demonstrated efficacy and safety in clinical trials to seal clear corneal incisions that can lead to leakage in patients after cataract surgery.(13) Omidria (phenylephrine 1% and ketorolac 0.3% combination) represents another agent that was approved in 2014 for the reduction of postoperative ocular pain.(259)

3. Recent Medicinal Chemistry Campaigns for Ocular Drug Discovery Programs

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This section presents recent medicinal chemistry campaigns for ocular drug discovery programs. The structure–activity relationship studies, along with other relevant details, are presented.

3.1. Drug Discovery Programs for AMD

3.1.1. RBP4 Antagonists

The synthetic retinoid drug fenretinide has demonstrated significant promise in preclinical studies to reduce the levels of circulating plasma RBP4 in vivo and bisretinoid production.(24) In light of these revelations, Angel et al. conducted structure–activity relationship studies to design retinoid analogues that can disrupt sRBP–TTR and sRBP–sRBP receptor interactions. Optimization of the fenretinide (28) chemical structure indicated that decreasing the length of the chain diminished the binding affinity to sRBP, which clearly indicates that polyene chain is critical for the interaction. The results led to the identification of several potent compounds (2934) that disrupted the sRBP–TTR and sRBP–receptor interactions. Though the inhibitors discovered in this study were anticipated to yield therapeutic benefits against type 2 diabetes, they possess enough promise for further investigations in AMD. A similar case was found for A1120, which was first developed for the potential treatment of diabetes; however, A1120 later emerged as a potent nonretinoid antagonist (Figure 12).(260)

Figure 12

Figure 12. Fenretinide derivatives.

Aligned with the aim of designing a nonretinoid-based RBP4 antagonist with improved HLM stability, Cioffi et al. explored novel, conformationally flexible, and constrained RBP4 antagonists employing A1120 (35) as the lead. Investigations began with acylsulfonamide carboxylic esters and aliphatic carboxylic acids (3638); however, the quest to identify more potent antagonists led to other structural alterations that maintained the anthranilic acid appendage. Subsequent modifications involved the replacement of the piperidine ring with acyclic and conformationally constrained motifs. The attempts yielded potent bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of RBP4 displaying striking in vitro potential. Compound 39 exhibited comparable potency to A1120 with a favorable ADME profile and good HLM stability. Compound 39 also decreased circulating plasma RBP4 protein levels in chronic and acute rodent oral dosing studies. It was quite intriguing to note that exo isomer 40 of compound 39 showed a dramatic loss in activity. Docking studies indicated that relative to the endo isomer, a highly strained geometry was adopted by the exo isomer, which might be a factor responsible for the difference in RBP4 binding affinity between the two isomers. Overall, it was observed that the anthranilic acid appendage of compound 39 is involved in key hydrogen bonding interactions within the RBP4 binding cavity. Further refinement of compound 39 via replacement of the arylcarboxylic acid phenyl ring of 39 with a pyridine or pyridazine moiety markedly influenced the RBP4 binding affinity. This modification culminated in the identification of pyridazine derivative 41 as a potent RBP4 antagonist (Figure 13).(261)

Figure 13

Figure 13. Non-retinoid based RBP4 antagonist.

Cioffi et al. continued their investigation on bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of RBP4 and employed compound 39 as a template for further structural explorations involving isosteric replacement of the anthranilic acid appendage with pyrimidine-4-carboxylic acid functionality. The initial subset of compounds synthesized retained the ortho-trifluoromethylphenyl headgroup of A1120 (35) and compound 39, which led to the identification of compound 37 as a stand-out analogue endowed with substantial in vitro RBP4 potency and excellent microsomal stability. Further delineation of the structural features of compound 42 involved investigation of the 6-methylpyrimidine-4-carboxylic acid region as well as the aryl headgroup. These attempts did not yield favorable results in terms of potentiating the activity of compound 42, however, provided insights in to the structure–activity relationship (SAR) of this class of RBP4 antagonists. A detailed biological evaluation of compound 42 revealed that it possesses significant RBP4 binding affinity. Compound 42 also caused a reduction in the circulating plasma RBP4 levels in vivo (Figure 14).(24)

Figure 14

Figure 14. RBP4 antagonists.

Wang et al. also reported potent nonretinoid ligands for RBP4 via structural optimization of the high-throughput screening (HTS) hits 43 and 44. This study also revealed that the inhibitors caused disruption of the RBP4–TTR interaction through induced loop conformational changes.(262) The structure–activity relationship studies conducted in this work led to the identification of A1120 (35), which exhibited concentration-dependent retinol and RBP4 reductions. Though this study holds significant importance in the context of identifying 35, the other potent structures (4350) shown in Figure 15 can be investigated in detail for their potential to treat atropic and Stragardt disease.

Figure 15

Figure 15. RBP4 ligands.

3.1.2. Complement Pathway Inhibitors

AMD is well reported to be associated with chronic dysregulation of alternative complement pathway (AP) activation. Several studies have ascertained that FD (factor D) inhibition is a logical mechanism to block complement AP.(263) Capitalizing on this available information, Maibaum et al. reported potent small-molecule reversible inhibitors employing a structure-based design approach coupled with fragment-based screening. The investigation initiated with the discovery of compound 51, which in the FD active site was found to occupy the buried S1 pocket and extend into the prime site (S1′–S2′). The orientation of kallikrein-7 (KLK-7)-bound 51, a related S1 serine protease, favored several hydrogen bonding interactions. These revelations laid the foundation for FD-tailored inhibitor design, and subsequently, a set of proline analogues of 51 was evaluated, which provided compound 52, with an IC50 value of 14 μM (FD). Further selection of 52 000 fragments and analyses of their docking in silico into a distinct FD active site conformation (PDB 1DIC) were carried out. The screening of the top scoring fragments by ligand-observation NMR (waterLOGSY) led to the identification of 53, whose water-soluble carboxylic acid analogue 54 was synthesized to ascertain binding and quantification of binding affinity. Subsequent investigations yielded the indole base scaffold 55, which was subjected to chemical optimization to develop aza indazoles 56a,b as potent inhibitors of FD. Overall, the results of this study provided various inhibitors that can significantly block AP activation and prevent PNH erythrocyte lysis as well as C3 deposition (Figure 16).(26)

Figure 16

Figure 16. Complement pathway inhibitors.

The same research group continued their investigation to identify noncovalent ligands as structurally varied hits bearing binding affinity to complement FD. Subsequently, the efforts collectively identified the ligands that bind to various subpockets of the latent FD conformation and provided clarity regarding the binding requirements to generate potent noncovalent reversible FD inhibitors for the first time (Figure 17).(27)

Figure 17

Figure 17. Complement pathway inhibitors.

The same research group extended their research work to develop therapeutics for AMD. In this investigation, the authors employed a design strategy that involved the merging of the key pharmacophoric subunits of two previously identified hits. The efforts yielded noncovalent FD inhibitor 63 as a lead compound, which was subjected to further structural optimization. Resultantly, selective, reversible and noncovalent FD inhibitors were identified. Moreover, sustained oral and ocular efficacy was demonstrated by a potent inhibitor 68 on detailed investigation in an LPS-induced systemic AP activation mouse model. Compound 68 was also found to possess in vivo efficacy, as evidenced in an FD knock-in mouse model, and after oral administration, 68 also blocked systemic AP activity in cynomolgus monkeys (Figure 18).(28)

Figure 18

Figure 18. Complement pathway inhibitors.

Karki et al. employed a structure-based approach to design selective FD Inhibitors. The research group had previously reported benzylamine-based FD inhibitors(264) that were able to target an active conformation of FD. As an extension of their research work, the authors conducted a structural optimization of a series of benzylamines, and an orally bioavailable and selective FD inhibitor 70 was identified. Upon evaluation in an LPS-induced AP activation model, the compound was found to be endowed with a promising activity profile causing a systemic suppression of AP activation. Studies conducted in an intravitreal injection-induced AP activation model revealed that the selective FD inhibitor also induced local ocular suppression D (Figure 19).(30)

Figure 19

Figure 19. Complement pathway inhibitors.

The same research group recently reported the first small molecular inhibitors of C-5 complement protein. The study initiated with the assessment of complement inhibitors 71 and 72, reported previously by Zhang et al.(265) for their interaction with the complement proteins using size exclusion chromatography coupled with mass spectrometric detection. The results were also supported by dynamic scanning fluorimetry that led the authors to establish that C5 is the pharmacological target of 71 and 72. The authors further employed a structural optimization program to improve the potency and solubility of these inhibitors. It was observed that placement of a hydroxyl group and a carboxylic acid group (compound 73) enhanced the solubility, while a 2-methoxy substitution on the terminal phenyl ring provided a > 30-fold increase in potency (compound 74) in comparison to compound 71. As a result of these revelations, the optimized structural features were combined to yield a potent inhibitor, 75, endowed with excellent potency as well as good aqueous solubility. Compound 75 demonstrated a half-minimum inhibitory concentration of 1 μM for the inhibition of MAC deposition, whereas both 71 and 72 were found to be inactive up to the concentration of 100 μM. Further investigations were carried out to confirm the molecular mode of inhibition for these C5 small-molecule inhibitors by cryogenic electron microscopy (Figure 20).(29)

Figure 20

Figure 20. Complement pathway inhibitors.

3.1.3. Inhibitors/Agents for Angiogenesis-Related Ocular Diseases

Anti-VEGF therapy (intravitreal) is a proven strategy to treat AMD. Despite the significant promise, systemic inhibition of the VEGF pathway is associated with side effects (on-target). To date, the majority of these efforts have been directed toward the screening of VEGFR-2 inhibitors approved for oncology to explore their potential in wet AMD. However, the systemic side effects have still been observed, despite using significantly lower doses than those used for oncology indications. This outcome indicates that compounds endowed with the potential to selectively target ocular tissues would be a more rational strategy to develop safer drugs for wet AMD patients. With this background, Meredith et al. conducted an iterative compound design study to identify compounds with preferential ocular distribution. To accomplish this, VEGFR-2 kinase inhibitors were screened in the mouse CNV model, and compound 76 was identified as a promising lead for the subsequent structural engineering program. The lead optimization study yielded compounds 7779, which exhibited markedly higher ocular exposure than plasma exposure. Preferential ocular tissue distribution was demonstrated by these compounds after oral administration while minimizing systemic exposure (Figure 21).(266)

Figure 21

Figure 21. VEGFR-2 inhibitor.

The same research group further expanded their drug discovery program in view of the use of repeated intravitreal injections to attain the desired therapeutic effects in the neovasculature, which is a difficult task for both clinicians and patients. In search of effective alternatives, Adams et al. conducted a lead modification study of several VEGFR-2 inhibitors (8082) that were developed previously for oncology indications along with agents developed for enhanced ocular exposure after oral delivery (8384). The screened compounds did not demonstrate significant inhibition of CNV when dosed topically, with indole-based compound 84 emerging as an exception, as it demonstrated in vivo efficacy upon topical administration. Thus, employing compound 84 as the starting point, the authors performed structure-based tailoring of the leads to discover VEGFR-2 inhibitors appropriate for ocular delivery (topical). The results of the investigation yielded VEGFR-2 inhibitor 85, which displayed striking potency and efficacy in the rat CNV model. Moreover, compound 85 possesses an acceptable toxicology as well as a rabbit ocular PK profile. This optimistic finding drove the progress of this agent toward clinical trial studies (Figure 22).(267)

Figure 22

Figure 22. VEGFR-2 inhibitors

Cremastranone is a homoisoflavone that inhibits ocular angiogenesis in mouse models of CNV. By employing cremastranone (86) as the starting point for structural optimization, Basavarajappa et al. planned modifications to the A and B rings of cremastranone to create homoisoflavanoid analogues endowed with higher selectivity for retinal endothelial cells. The study results revealed that the most potent analogue, 87, bearing a phenylalanyl moiety, displayed substantial activity and striking selectivity for retinal endothelial cells. Furthermore, remarkable antiangiogenic efficacy was exhibited by compound 87 in an oxygen-induced retinopathy model. Overall, this study may initiate extensive explorations of the flavone and isoflavone frameworks to attain therapeutic benefits for eye diseases (Figure 23).(268)

Figure 23

Figure 23. Homoisoflavanoid analogues.

Palanki et al. synthesized benzotriazine-based compounds bearing the potential to inhibit Src and VEGFR2. Both mechanisms are well-known to mediate a crucial role in AMD. The initial in vitro screening identified compound 88 as a potent inhibitor; however, this compound was unable to attain a sustained concentration in certain back-of-the-eye tissues. To address this limitation, a prodrug strategy was employed, which yielded a topically administered prodrug displaying rapid conversion to 88 in the eye. Prodrug 89 was endowed with excellent ocular pharmacokinetics with significant efficacy in the laser-induced CNV model. These promising results led to the progression of prodrug 89 to clinical studies for the treatment of AMD (Figure 24).(269)

Figure 24

Figure 24. Benzotriazine-based compounds.

In view of the critical role of angiogenesis in wet AMD and proliferative DR, Olivieri et al. designed a prodrug (90) via conjugation of haloperidol metabolite II (a sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) to an HDAC inhibitor (valproic acid) through an ester bond. The prodrug displayed antiangiogenic activity comparable to bevacizumab and significantly reduced endothelial cell migration, viable cell count, and tube formation in VEGF-A-stimulated human retinal endothelial cell cultures. The results of the study were extremely promising and optimistic, particularly for diseases related to angiogenesis (Figure 25).(270)

Figure 25

Figure 25. Prodrug of haloperidol metabolite II.

Exploration of the mechanisms involved in ocular diseases revealed that somatostatin receptor subtype 2 (sst2) agonists hold enough promise and optimism as therapeutics for ocular angiogenic diseases.(271) To expand the utility of sst2 agonists, Wolkenberg et al. performed a high-throughput screen of the Merck screening collection, which culminated in the identification of compound 91 (a potent gonadotropin-releasing hormone (GnRH) antagonist) as a modest sst2 binder. The optimization strategy employed intended to develop small molecules with sst2 binding and a comparable functional potency to peptide agonists. The study led to the identification of agonist 96, which inhibited rat growth hormone secretion following systemic administration. The capacity of agonist 96 to inhibit ocular neovascular lesion was investigated in a rat laser-induced CNV model, and the results demonstrated that the intraocular administration of 96 induced a dose-dependent antiangiogenic effect and inhibited ocular neovascular lesion formation (Figure 26).(272)

Figure 26

Figure 26. sst2 agonists.

The role of hypoxia-inducible factor (HIF) in the pathogenesis of many ocular diseases has been well explored.(273) Recent explorations have revealed that regulating factors upstream of VEGF, such as HIF-1α, are logical therapeutic strategies. In light of this valuable information, An et al. conducted a structural feature elucidation approach to synthesize ring-truncated analogues of deguelin with potent HIF-1α inhibitory activity. Previous attempts by the same research group reported the potential of deguelin (97) to interfere with ATP binding to the chaperone protein HSP90.(274) Their continued explorations in this field yielded ring-truncated deguelin analogues SH-1242 (98) and SH-1280 (99), displaying potent inhibitory activity toward HIF-1α, which is an HSP90 client protein.(275) An extended investigation involved the structural diversification of ring-truncated analogues 100 and 101. The results made an exciting revelation regarding analogue 102, which was endowed with higher HIF-1α inhibitory activity in comparison to 92 and inhibited angiogenesis in vitro. Analogue 102 also induced suppression of hypoxia-mediated retinal neovascularization in an effective manner. In addition, compound 103, displaying a 20-fold higher HIF-1α inhibitory effect than 102, was also an important finding of the study (Figure 27).(276) Overall, the study led to the identification of a novel HIF-1α inhibitor for angiogenesis-related ophthalmic diseases.

Figure 27

Figure 27. HIF-1 α inhibitors.

3.1.4. Others

Jin et al., in search of multifunctional antioxidants as potential ocular therapeutics, synthesized N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamides (104). The designed compounds bear a free radical scavenging group, a chelating group, or both and were evaluated in human lens epithelium, human hippocampal astrocyte cell lines, and human retinal pigmented epithelium. The results of the study were quite optimistic, as some of the compounds were found to protect these cells against decreased cell viability and reduced hydrogen peroxide-induced glutathione levels, while some compounds protected the cells against Fenton reaction-mediated generation of hydroxyl radicals (Figure 28).(277)

Figure 28

Figure 28. Multifunctional antioxidant as potential ocular therapeutics.

Joshi et al. designed inhibitors of A2E photooxidation in view of the role of A2E in macular degeneration. The synthetic strategy employed the utility of the Mannich reaction of quercetin (an antioxidant). Compound 105 possessed a water-solubilizing amine group imparting drug-like physiochemical properties and was found to be endowed with superior efficacy for the inhibition of A2E photooxidation compared with quercetin (Figure 29).(278)

Figure 29

Figure 29. Inhibitors of A2E photooxidation, hypocrellin derivatives as photosensitizers for photodynamic therapy.

Deng et al. reported hypocrellin derivatives as photosensitizers for the photodynamic therapy of AMD. The study was inspired by the fact that hypocrellin, belonging to the general class of perylene quinonoid pigments, possesses ideal characteristics as a photosensitizer. Derivatives 106 and 107 exhibited their maximum absorption at approximately 580 nm, which is considered to be the proper phototherapeutic window for AMD. Moreover, both compounds had good aqueous solubility, which can allow intravenous administration (Figure 29).(279)

3.2. Drug Discovery Program for Glaucoma

3.2.1. Carbonic Anhydrase (CA) Inhibitors

Carta et al. designed, synthesized, and evaluated dithiocarbamates for the inhibition of CA. The results demonstrated a dithiocarbamate (108) inhibiting the hCAII isoform (involved in glaucoma) at nanomolar concentrations and exhibited substantial IOP-lowering potential activity in a glaucoma animal model.(280) The same research group further extended the work by synthesizing xanthates and trithiocarbonates. The results of the study were quite promising, as low nanomolar xanthate/trithiocarbonate-based CA inhibitors were identified. Further evaluations (in vivo studies) conducted in normotensive/hypertensive rabbits revealed that xanthanes (109, 110) endowed with substantial inhibitory potential against the hCA II isoform caused significant lowering of IOP on direct administration within the eye.(281) The docking studies revealed that both dithiocarbamates as well as xanthates displayed similar binding patterns and coordinated monodentately to the Zn(II) ion.(280,281) Overall, the outcomes of these investigations presented dithiocarbamates and xanthates as promising classes of CA inhibitors with antiglaucoma effects (Figure 30).(280,281)

Figure 30

Figure 30. CA inhibitors.

In continuation of their investigation on CA inhibitors with antiglaucoma effects, the same research group reported monothiocarbamates as CA inhibitors. The monothiocarbamates displayed pronounced effects against hCA, IX, and XII. The most potent compounds were evaluated in an acute glaucoma animal model, and the results revealed that compound 111 possessed excellent potency to lower the IOP within a period of 120 min, while compounds 112 and 113 retained their effect up to 240 min. Overall, the study concluded that monothiocarbamates as CA inhibitors hold enough promise as antiglaucoma agents for further investigations (Figure 31).(282)

Figure 31

Figure 31. Monothiocarbamates as CA inhibitor.

Bozdag et al. reported 4-sulfamoylphenyl-ω-aminoalkyl ethers as potent CA inhibitors. Docking studies were conducted, which depicted that the tails of these compounds were bound in the hydrophobic half, leading to van der Waals interactions with amino acids. The results yielded a potent IOP-lowering agent 114, as evidenced by the outcome of the study conducted in the animal model of glaucoma (Figure 32).(283)

Figure 32

Figure 32. CA inhibitors.

Bozdag et al. further extended their study on CA inhibitors with an aim to identify potent antiglaucoma drugs. The results of the biological evaluation revealed that sulfonamide derivatives bearing the pyridinesulfonamide moieties and arylsulfonyluoreido fragments exhibited remarkable inhibitory activity profiles against the isoforms upregulated or overexpressed in glaucoma. The inhibitory behavior was studied at the molecular level by observing the X-ray crystal structures of some of the inhibitors bound to hCA II. Among all the compounds, two of these compounds, 115 and 116, demonstrated substantial in vivo antiglaucoma activity with higher efficacy than the clinically used drug dorzolamide (Figure 33).(284)

Figure 33

Figure 33. CA inhibitors.

Carta et al. prepared poly(amidoamine) (PAMAM) dendrimers by the condensation at the amino groups(dendrimer) with 4-carboxy-benzenesulfonamide moieties. Some of the compounds were found to be potent inhibitors of isoforms CA II and XII and exerted significant lowering of IOP on chronic administration in animal models of glaucoma (Figure 34).(285)

Figure 34

Figure 34. CA inhibitors.

Influenced by the design of sulfonamide inhibitors,(286) Nocentini employed click chemistry to synthesize benzenesulfonamides bearing phenyl-1,2,3-triazole moieties. The designed strategy involved the inclusion of appropriate molecular fragments to obtain a flexible arrangement in comparison to the previously reported phenyltriazolylbenzenesulfonamide (118),(287) which possessed low conformational freedom. The authors explored the incorporation of ether, thioether, and amino functionalities as appropriate linkers to induce additional flexibility. Several compounds (119121) were endowed with low nanomolar or subnanomolar hCA II, IX, and XII inhibition activity. The experimental results were further rationalized by computational and X-ray crystallographic studies. Compounds 119121 were found to be endowed with substantial IOP-lowering activity in a glaucoma animal model (Figure 35).(288)

Figure 35

Figure 35. Benzenesulfonamides bearing phenyl-1,2,3-triazole moieties.

The recent success of molecular hybridization techniques in the development of therapeutics for diverse complications inspired a group of researchers to design hybrid scaffolds for multitargeted antiglaucoma therapy. Anticipating the benefits of synthesizing chemical architectures capable of interacting with both β-adrenergic and CA, Nocentini et al. synthesized two series of benzenesulfonamides incorporating benzenesulfonamide fragments of classical CA inhibitors and 2-hydroxypropylamine fragments of known and clinically used β-blockers. In one of the series, an aryloxy-2-hydroxypropylamine portion was directly attached, while an ethylbenzamide spacer was utilized in the second series. The resulting hybrids 122, 123, and 124 exhibited more pronounced IOP-lowering activity than dorzolamide and timolol as well as the combination of these two drugs in glaucoma animal model. The results of the study ascertain the promising attributes of β-adrenergic receptor blocker–CA inhibitor hybrids that exert IOP-lowering effects through an innovative mechanism of action (Figure 36).(23)

Figure 36

Figure 36. Hybrid scaffolds as antiglaucoma drugs.

To maximize the IOP-lowering efficiency, Huang et al. synthesized an NO donor containing CA inhibitors with an aim to develop constructs with a dual mechanistic approach: (i) decreasing the aqueous humor secretion via inflow reduction by CA inhibition and (ii) increasing aqueous humor drainage via increased outflow by NO release. The design strategy utilized the placement of a nitro group to act as an NO donor that was incorporated in the alkyl side chains of dorzolamide and brinzolamide. The outcome of the study identified two potent IOP-lowering agents, NO-dorzolamide 125 and NO-brinzolamide 126, which demonstrated improved IOP-lowering efficacy in comparison to brinzolamide in both rabbits and monkeys. The OHTN primate tonometry revealed significant improvement in efficacy, indicating the potential of dual mechanism inhibitors as IOP-lowering agents (Figure 37).(289)

Figure 37

Figure 37. CA inhibitors.

3.2.2. ROCK and LIM Kinase Inhibitors

ROCK, as a proven attractive antiglaucoma target, has led to the initiation of several structure–activity relationship studies. Working on similar lines, Yin et al. synthesized a series of urea-based chemical architectures in their quest to develop ROCK II inhibitors. Among the compounds synthesized, compound 129 exhibited substantial IOP-lowering potential on testing in rat eyes.(173) Continuing their investigation, the same research group further explored urea scaffolds to afford multipoint diversification and enable the manipulation of the pharmaceutical properties of the inhibitors. The subsequent efforts led to the identification of two subsets of compounds, one (without a tertiary amine group, 130133) with good in vivo properties as a potential agent for systemic applications and another (possessing a tertiary amine group, 134136) with poor PK properties but good aqueous solubility that was anticipated to be a good chemotype for topical applications (Figure 38).(290)

Figure 38

Figure 38. ROCK II inhibitors.

Capitalizing on the proven potential of ROCK inhibitors in glaucoma, Fang et al. synthesized tetrahydroisoquinolines and identified a substantially potent and selective inhibitor 137, which demonstrated IOP-lowering activity in rat eyes (Figure 39).(291)

Figure 39

Figure 39. Tetrahydroisoquinolines as ROCK inhibitors.

Attempts to discover potent ROCK inhibitors led to the identification of the potent isoquinoline-based compound 138. Despite the satisfactory potential, this compound suffered from limitations such as poor oral bioavailability and poor in vitro microsomal stability.(292) The scaffold identified was further subjected to structural optimization for dual ROCK1/ROCK2 inhibition, and N-dealkylated analogue 139, with improved microsomal stability and intact potency, was discovered. Despite this optimistic and promising activity profile, a dramatic loss in potency in an aortic ring relaxation assay was observed. Decreased lipophilicity and increased H-bond donor count were anticipated as possible reasons for this dramatic loss.(293) The authors further expanded the SAR, which revealed that compound 140, bearing a piperidine ring, sustained blood pressure normalization (Figure 40).(294)

Figure 40

Figure 40. Isoquinoline-based ROCK inhibitors.

Efforts by Henderson et al. explored a focused kinase library for structure–activity relationships, which led to the identification of several 2,3-diaminopyrazines as ROCK inhibitors. Among the series, compound 141 displayed an interesting and favorable in vitro activity profile that was endowed with significant efficacy in the in vivo studies (monkey), decreasing the IOP by an average of 33% (300 μg dose) and 37% (600 μg dose).(130) A further in vivo optimization study on ROCK inhibitors bearing the 2,3-diaminopyrazine scaffold for topical ocular dosing was performed by Chen et al.; SAR studies revealed that structural engineering attempts on the 2-(piperazin-1-yl)pyrazine moiety culminated in the identification of derivatives with improved solubility and physicochemical properties. It was also observed that the improved in vitro potency was induced by diversification of the 6-pyrazine substituent. Compound 142 was the standout compound of the series, inducing a 30% IOP reduction in a nonhuman primate model.(131) Li et al. discovered fragments to inhibit Rho-associated kinases by structure-guided design. The optimization of ROCK inhibitors was aided by molecular modeling studies. The efforts identified dual ROCK1/ROCK2 inhibitor 143 and the selective ROCK2 inhibitor 144. Further studies and investigation of the compound 143–ROCK1 complex indicated that 143 binds to the hinge region in the ATP binding site and is a type 1 inhibitor.(295) Chroman-3-amide scaffolds have also been explored and were found to possess selective ROCK2 inhibitory potential with good microsomal stability and desirable pharmacokinetic properties. A docking study of inhibitor 145 into the catalytic domain of ROCK II was instrumental in inducing ROCK II inhibition via an interaction with a hydrophobic binding region composed of Phe103 of the flexible P loop, Leu123, the carbon chain of Lys121, and Phe136.(296) Boland et al. designed ROCK inhibitors that were structurally related to the Y-27632. Attempts were made to overcome the ROCK-associated side-effects evidenced as a hindrance to the clinical progress of ROCK inhibitors. The study results were quite optimistic, with compound 146 exhibiting strong ROCK2 inhibition with rapid inactivation in plasma coupled with substantial in vivo IOP-lowering potential without ocular side effects.(297) Feng et al. also discovered ROCK-II inhibitors bearing a pyrazole group that was anticipated to function as a hinge-binding moiety. Biological evaluations led to interesting findings, with compound 147 exhibiting potency in both enzyme- and cell-based assays. Further delineation of its activity profile revealed that compound 147 (SR-3677) was effective in increasing AH outflow and the on-target decrease in p-MLC levels (Figure 41).(132)

Figure 41

Figure 41. Rock inhibitors.

Capitalizing on the revelations that LIM kinases are downstream of ROCK in the signaling pathway,(109,195) Harrison et al. carried out a lead optimization study of a pyrrolopyrimidine compound 21 (lead compound) identified through high-throughput screening. Compound 21 appeared to be a strong candidate due to its activity profile along with an accessible and amenable chemical architecture suitable for structural diversification. SAR studies were performed, and extensive attempts were made to increase the structure pool. Attempts led to discovery of pyrrolopyrimidine class of LIMK2 inhibitors endowed with good potency in enzymatic/cellular assays and substantial selectivity against ROCK. On administration, compound 22 (aqueous formulation) caused a significant IOP reduction in the eyes of OHTN mice. Moreover, compound 22 also increased the outflow capacity in pig eye perfusion assays. Overall, the study validated LIMK2 as a potential target for glaucoma treatment.(196) In continuation of their drug discovery program to develop therapeutics for glaucoma, the same research group designed dual LIM kinase and ROCK inhibitors. The design strategy employed compound 22 as the lead, and structural optimization was carried out. The reason for the structural engineering of compound 22 was attributed to its poor aqueous stability owing to solvolysis of the central urea moiety. To overcome this issue, structure–activity relationships were established for the solvolysis reaction to produce stable, active compounds. The structural alterations of inhibitor 22 were strategized to overcome the aqueous instability due to the central urea in 22 and to enhance the aqueous solubility. Replacement of the piperazine ring of 22 with a substituted piperidine yielded 23 (LX7101), displaying significant efficacy in a mouse model of OHTN. LX7101 (23) advanced to a phase 1 clinical trial, and it was found to replicate the IOP-lowering efficacy (Figure 42).(197)

Figure 42

Figure 42. LIM-Kinase and ROCK inhibitors.

3.2.3. Others

Blangetti et al. reported gem-dinitroalkyl benzenes as IOP-lowering agents with varying NO-release capacities. The compounds were evaluated in a transient OHTN rabbit model, and it was observed that some of the compounds were endowed with potent IOP-lowering effects similar to that of molsidomine (an orally active, long-acting vasodilating drug used to treat angina pectoris). The compounds demonstrated the capacity to relax contracted rat aorta strips. Out of all the compounds, two compounds, 151 and 152, also caused significant reductions in a chronic model of IOP (carbomer-induced glaucoma) (Figure 43).(298)

Figure 43

Figure 43. gem-Dinitroalkyl benzenes as IOP lowering agents.

Recent revelations ascertain the contribution of dysregulated sGC/NO/cGMP in elevating the intraocular pressure associated with glaucoma. Emphasizing these findings and reports, Ehara et al. conducted an interesting study to discover molecules suitable for topical ocular administration that can activate oxidized sGC and restore the capacity of sGC to catalyze cGMP production. The starting point of the investigation was the design of compound 153 inspired by an HTS hit. The chemical architecture of compound 153 involves thiophene and piperidine rings as the key structural motifs. The subsequent investigation revolved around the optimization of compound 153, employing it as a lead compound. The attempts led to the discovery of compound 154, which, on administration as single topical ocular drop, could lower IOP in a cynomolgus model of elevated IOP over 24 h (Figure 44).(299)

Figure 44

Figure 44. Compounds for topical ocular administration.

Recent reports indicate that EP2 receptor agonists are endowed with the potential to lower IOP and have promising attributes for the treatment of glaucoma.(198) Motivated by these revelations, Iwamura et al. conducted a lead modification study on a selective EP2 receptor agonist, CP-533,536 (24). The selection of CP-533,536 as the viable starting point for structural engineering was heavily influenced by the ongoing clinical trials imparting promising anticipation in the context of its efficacy and safety. The subsequent medicinal chemistry efforts identified compound 25 as having potent as well as selective activity toward the human EP2 receptor. The prodrug (155) of compound 25 at low concentrations also displayed an interesting activity profile and lowered IOP in ocular normotensive monkeys. These results demonstrated that the prodrug may emerge as an effective ocular hypotensive agent for glaucoma treatment (Figure 45).(199)

Figure 45

Figure 45. Selective EP2 receptor agonist.

In view of the reported potential of selective 5-HT2 receptor agonists to effectively reduce the IOP in glaucoma, several studies were conducted by May et al. to design selective 5-HT2 receptor agonists. As a result, agonists 156158 were identified; however, several limitations urged the authors to design structure–activity relationship studies. Compound 156 (a selective 5-HT2A receptor agonist) exhibited significant efficacy in a nonhuman primate model of OHTN, along with desirable physicochemical and permeability profiles, but it was found to be endowed with cardiovascular side effects. Pyrano[3,2-e]indole (157, a selective 5-HT2A receptor agonist) lacked acceptable solution stability, while pyrano[2,3-g]indazole (158, a selective agonist for the 5-HT2 family of serotonin receptor agonists possessing the highest binding affinity for the 5-HT2C subtype) displayed enhanced solution stability; however, CNS permeability was an issue. Subsequent alterations in the chemical architecture led to the identification of pyrano[2,3-g]indazole (159), with a profile favorable for detailed preclinical evaluation for the treatment of OHTN (Figure 46).(300,301)

Figure 46

Figure 46. 5-HT 2 receptor agonists

3.3. Drug Discovery Program for Cataract

Glikman conducted a screening of drug candidates that could decrease human lenticular protein aggregation, and the results revealed that rosmarinic acid is a potent cataract modulator. Rosmarinic acid (160) exhibited better optical clearance and reduction of amyloid content in comparison to sterols. Further mechanistic studies were performed, and it was found that rosmarinic acid deterred cataractogenesis in model rats. The revelations supported the concept that the modulation of protein aggregation can lead to the amelioration of cataract formation in vivo and presents the potential of 160 as a potential agent for cataract treatment (Figure 47).(302)

Figure 47

Figure 47. Rosmarinic acid as a potent cataract modulator.

Taking the lead from a study that reported the in vitro aldose reductase inhibitory activity and antidiabetic effects of the natural product emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione), Chang K.E., et al. investigated the protective role of emodin (161) in the prevention of diabetic cataract formation. They found that emodin was thermally stable at 37 °C and uncompetitively inhibited aldose reductase with an IC50 value of 2.69 ± 0.90 μM. Emodin was found to reduce vacuole formation, the efficacy of which was higher when used as prophylactic. In the molecular modeling analysis, they found favorable interactions within the active site of human AKR1B1 (PDB 2FZD) and observed that the binding pose of emodin (161) was similar to that of β-glucogallin, which is a selective and well-characterized aldose reductase inhibitor (Figure 48).(303)

Figure 48

Figure 48. Emodin as aldose reductase inhibitor.

Inspired from the established aldose reductase inhibitor Tolestat (an acetic acid derivative) and various previous outcomes of acetic acid derivatives in aldose reductase inhibition, Da Settimo et al. prepared acetic acid derivatives of naphtho[1,2-d]isothiazole as aldose reductase inhibitors. Among the series of compounds developed, 162 showed the most potent inhibitory potential. They evaluated the preventive action of compounds against cataract development in galactosemic rats and observed that compound 162 did not show any protective effect, but its prodrug, 163 (isopropyl ester), exhibited protection comparable to tolrestat due to increased permeability resulting from higher lipophilicity. A molecular modeling (PDB 1AH3) study suggested that hydrophobic interactions of 162 with the active site are responsible for its selectivity (Figure 49).(304)

Figure 49

Figure 49. Naphtho[1,2-d]isothiazole as aldose reductase inhibitors.

3.4. Drug Discovery Program for Diabetic Retinopathy, Macular Edema, and Dry Eyes

Teufel D.P., et al. developed bicyclic peptides as plasma kallikrein inhibitors. These peptides were able to block the release of plasma bradykinin in both plasma and vitreous humor. One of the designed peptides showed superior efficacy when compared with indomethacin in the diabetic rat paw edema model. This peptide was demonstrated to be nontoxic up to 0.43–0.60 mg/kg in rats with a t1/2 of 48 min. This peptide showed a 30% decrease in retinal vascular leakage in diabetic rats, which was comparable to the soluble VEGF-trap positive control (Figure 50).(305)

Figure 50

Figure 50. Plasma kallikrein inhibitors.

Considering the role of vascular adhesion protein-1 (VAP-1) in the development of macular edema, Inoue T., et al. prepared novel thiazole derivatives as potent VAP-1 inhibitors using high-throughput screening and optimizing the lead hit via molecular docking (PDB 2C11) to target DME. Among the synthesized compounds, 165 was identified as the most potent VAP-1 inhibitor, with an IC50 value of 0.23 μM, with a good inhibitory effect on ocular permeability in STZ-induced diabetic rats. However, these compounds suffered from lower activity against human VAP-1. To overcome this issue, they redesigned 165 via observation of the SAR and molecular modeling. The resulting compound, 166, was a potent human VAP-1 inhibitor with an IC50 value of 0.019 μM that had 580-fold selectivity toward VAP-1 when compared with MAO-A/B (Figure 51).(306)

Figure 51

Figure 51. Thiazole derivatives as potent VAP-1 inhibitors.

In 2018, Jose et al. reported the neuroprotective effects of hydroxytyrosol (167) in diabetic retinopathic rats. In type I diabetes mellitus animals, the effect of compound 167 on the retinal tissue was analyzed. The results revealed that hydroxytyrosol did not modify blood glucose in diabetic animals. After the induction of diabetes in rats, retinal ganglion cells were reduced to 40%, and their levels decreased further after treatment with compound 167, i.e., 34% with 1 mg/kg and 9% with 5 mg/kg. It is also noteworthy that a 5 mg/kg/day dosage of compound 167 significantly influenced the retinal ganglion cell count (Figure 52).(307)

Figure 52

Figure 52. Hydroxytyrosol and mononaphthotrisulfobenzoporphyrazines photosensitizers.

Van Lier et al. reported water-soluble, mononaphthyltrisulfobenzoporphyrazine photosensitizers composed of an alkynyl side chain with varying lengths on the naphthyl ring. The results of the biological evaluation revealed that the derivative with a hexynyl side chain in conjunction with red light significantly inhibited plasma extravasation from retinal vessels and displayed significant activity. Overall, 168 displayed substantial potential as a photosensitizer for the treatment of retinal edema (Figure 52).(308)
It has been previously reported that compound 169 is a significant cystic fibrosis transmembrane conductance regulator (CFTR) activator, with an EC50 value of 250 nM for the treatment of dry eyes.(309) However, the repeated administration of 169 that was required to treat the disease condition urged Lee et al. to initially evaluate 91 commercially available triazine analogues to test their CFTR function. The 2,4,6-trisubstituted triazines contained R1, R2, and R3 substitutions, and it was found that a fluorinated alkoxide (R1), an aniline (R2), and an alkylamine (R3) provided the best results. In particular, compounds with para-substituted anilines on R2 and short alkylamine groups on R3 were found to be most preferable for CTFR activation. After further modification of the compounds, they found two prominent compounds with the strongest CFTR activation, 170 and 171, with respective EC50 values of 30 and 31 nM. Further off-target effects for these two compounds were also tested on cAMP and cytoplasmic calcium, which revealed that 170 and 171 did show these off-target effects. These compounds were further evaluated for their metabolic stability and cellular toxicity. The Alamar Blue assay revealed that the compounds were nontoxic, even at a concentration of 100 μM. For assessment of their metabolic stability, the compounds (μM) were maintained with rat hepatic microsomes. Compounds 169 and 171 were found to be metabolized rapidly, <40% at 15 min, while compound 170 was metabolized more slowly, 60% at 60 min. It is also noteworthy that compound 170 showed a longer lasting effect to increase the tear volume, i.e., 8 h, when 2.5 μL was given in an ophthalmic vehicle. In this regard, 170 and 171 demonstrate promise for further preclinical development (Figure 53).(310)

Figure 53

Figure 53. CFTR activators.

3.5. Other Drug Discovery Programs

The recognition of small structures by using visualizing agents in vitreoretinal ophthalmic surgery is currently a major challenge. Indocyanine green, which has several drawbacks, such as a toxic response to the macula causing irritation and that it must be applied at high concentrations for visualization, has previously been used by various surgeons.(311) To improve the visualization effect, Langhals et al. targeted cyanine dyes due to their strong light absorption, limited stability, and a matched light absorption expected for pentamethin cyanine dyes. Various dyes have been synthesized and evaluated for their red fluorescence and illumination. Dyes 172 and 173 were found to be significant binders to stain the basement membrane. Compound 174 was found to be a promising dye that showed strong fluorescence and was most effective for staining. It was also suitable for the optical detection of both absorption and fluorescence. These dyes were also found to be stable in ionic solutions, which confirmed that they are not metabolized and do not produce toxic effects such as indocyanine green. Therefore, these dyes may be of future interest for ophthalmic surgeons (Figure 54).(312)

Figure 54

Figure 54. Cyanine dyes.

Uddin et al. designed and synthesized the hypoxia-responsive molecular optical fluorescence imaging probe HYPOX-3 (175),(313) which was highly retained in hypoxic cells, contained a near-infrared (NIR) dye coupled with Black Hole Quencher 3 (BHQ-3, an efficient fluorescence quencher that cleaves azo-bonds via an azoreductase moiety)(314) and was used for imaging retinal hypoxia. The HYPOX-3 probe was tested to determine its capacity to cause apoptosis by using a caspase-3 enzyme assay, and the results indicated that it was not toxic to R28 retinal neuronal cells. To further confirm their selectivity and specificity, microscopy of 175 was carried out by incubating R28 cells with 175. It was found that the probe was activated in hypoxic cells. An in vivo evaluation of the probe was carried out by using a mouse model of laser-induced CNV, and the results revealed that 175 possessed the capacity to image hypoxic retinal cells and tissues (Figure 55).(25)

Figure 55

Figure 55. Hypoxia responsive molecular optical fluorescence imaging probe.

4. Ocular Drug Delivery (ODD)

ARTICLE SECTIONS
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4.1. Ocular Barriers and Physicochemical Properties of Drugs Affecting ODD

The eye is a complex organ with anatomical and physiological barriers that makes ODD challenging.(315) The barriers, including the corneal barrier, systemic absorption from the conjunctival sac, the blood–ocular barrier, and the blood–retina barrier, limit drug penetration into the eye. A number of physicochemical properties of a drug molecule, such as molecular weight, size, and surface charge, can further impact drug absorption via the ocular route. Collectively, the unique anatomical barriers of different parts of the eye as well as certain physicochemical properties of the drug molecule significantly affect the drug transport postocular administration. (Figure 56)

Figure 56

Figure 56. Physicochemical properties of drugs affecting ODD.

The cornea is a transparent collagenous structure with a thickness of approximately 0.5 mm and is considered the most critical barrier for drug penetration. After maturation, the epithelium forms a tight diffusion barrier for drug delivery to the anterior chamber. Matured epithelium possesses paracellular pores (2.0 nm diameter) that allow penetration of drug molecules with molecular weights of less than 500 Da. Corneal epithelium and endothelium allow the entry of small lipophilic molecules into the AH while restricting the entry of hydrophilic drug molecules. A number of approaches, including iontophoresis,(316) prodrugs,(317) ion-pair forming agents,(318) and cyclodextrins,(319) have been used to improve corneal drug permeation. Unlike the corneal epithelium and endothelium layer, corneal stroma allows the penetration of hydrophilic drug molecules while restricting the passage of lipophilic drug molecules through it. Thus, the anatomical design of the cornea strategically restricts the entry of both hydrophilic and lipophilic drug molecules. Interestingly, it has been found that small drugs with optimal lipophilicity with log D values ranging from 2 to 3 can penetrate these layers to enter the aqueous humor.(320) The corneal surface is found to be negatively charged under physiological conditions; thus, cationic compounds can easily bind to it. This corneal attachment of the cationic molecules improves the residence time of the cationic drug molecules and improves their bioavailability. Therefore, a number of positively charged novel drug delivery systems (DDS) such as nanoparticles, liposomes, and emulsions have been successfully developed for corneal drug delivery. Tseng et al. evaluated the potential of positively charged (zeta potential: +33 mV) gelatin nanoparticles for corneal drug delivery in animal models using fluorescent dye as a model drug. It was found that gelatin nanoparticles were efficiently adsorbed on the negatively charged cornea without any sign of eye irritation and were found to be retained in the cornea for a longer time.(21) Cationic lipid nanoparticles were prepared by Wang et al. for ODD of two model drugs, including Puerarin and scutellarin. The pharmacokinetic study revealed that cationic liposomes resulted in 2.33- and 2.32-fold increases in drug concentration in the AH for PUE and SCU, respectively, compared with drug solutions.(321)
The conjunctiva possesses an almost 17 times larger surface area than the cornea and plays a significant role in drug absorption. Additionally, the conjunctival epithelium is more moderately packed than the cornea, and it allows permeation of even higher molecular weight (up to 10 kDa) drug molecules. Again, contrary to the cornea, the conjunctiva is more permeable (∼55-fold) to hydrophilic drug molecules. However, drug absorption through this route is still limited owing to the presence of conjunctival blood capillaries and lymphatics.(322) Ocular drug bioavailability by this route is low due to loss of drug in the systemic circulation. Hence, conjunctiva can be a potential target for systemic drug delivery via the ocular route.
The human sclera is also a very interesting part of the human eye, having a large surface area of approximately 16.3 cm2. The sclera is composed of collagen fibrils, and glycoproteins,(323) comprising an easier gateway for solutes than the cornea and the conjunctiva. It acts as a special entrance for hydrophilic compounds due to their easy diffusion through the porous spaces within the collagen network or aqueous medium of proteoglycans.(324,325) However, similar to any other ocular structure, trans-scleral drug permeability is also significantly influenced by the molecular weight and surface charge of the drug molecules. In contrast to the cornea, positively charged drug molecules are less permeable to the sclera due to their binding to the negatively charged proteoglycan matrix of the sclera. However, negatively charged molecules are more permeable through it.(326)
The exact mechanism of drug permeation through the sclera is still not clear, making it difficult to predict the rate of trans-scleral drug delivery. Ambati et al. found that permeation of globular protein with a molecular radius of approximately 5.23 nm was higher than linear that of structured dextran of the same molecular weight but with a molecular radius of approximately 8.25 nm.(327) This finding indicates that charge-, molecular structure-, and molecular weight-based predictions of drug permeation behavior through sclera are not possible(328) and that extensive research in this area is still needed.
The choroid is another dynamic barrier to ODD due to its highly vascularized structure. It is composed of a network of fenestrated capillaries supplying blood to the retina, which is further supported by a thin (2 to 4 μm), pentalamellar, elastic Bruch’s membrane. The Bruch’s-choroid (BC) complex acts as a critical barrier to the delivery of drugs through the transscleral route than the sclera. Positively charged lipophilic solutes bind to the BC complex, which acts as a slow-release drug depot.
The retina and blood–retinal barrier are also considered as significant barriers to ODD. Reports reveal that penetration of larger drug molecules is even more difficult;(329,330) carboxyfluorescein, being a smaller molecule, could easily cross the retina from the subretinal space to the vitreous within 2 h. However, a study revealed that dextrans with molecular weights including 70 kDa (58 Å) and 150 kDa (85 Å) took 72 h to penetrate through it.(331) The BRB mainly restricts the entry of the systemic circulation into the retina.(332) The tight junctions of the BRB selectively hinder the entry of hydrophilic compounds and macromolecules to the retina from the blood circulation.(333,334)
Drug diffusion across the RPE is more significantly impacted by molecular radius than molecular weight. The rate of drug permeation decreases with the increase in the molecular radius of the drug molecules. Pitkanen et al. found that carboxyfluorescein (376 Da; 5 Å) is 35-fold more permeable through the RPE than dextran (80 kDa; 64 Å). It was found that both hydrophilic and lipophilic drugs can permeate through the RPE following different molecular pathways. Hydrophilic compounds were found to mainly follow the paracellular route, whereas lipophilic drugs follow the transcellular route to permeate via RPE.(335) Taken together, these barriers are important parameters that control the design of DDS.(336)

4.2. Drug Delivery Routes

The anatomical and physiological barriers are the primary obstacles that limit the delivery of ocular drugs, and administration of ocular drugs via local or systemic routes must overcome the barriers to attain effective concentrations in the retina and vitreous humor.

4.2.1. Routes of Drug Delivery to the Anterior Segment

Topical administration is the most convenient, preferred, and conventional route for anterior segment disorders. This route is noninvasive and painless and presents many advantages, such as fast effect, small required dose, and no systemic adverse effects induced. However, poor patient compliance, repeated dosing and rapid washout by tears and limited penetration are the limitations associated with this route.(337)
Intracameral administration, a local drug delivery method, is an alternative practice for the direct injection of drugs to the anterior segment of the eye. It avoids the side effects that occur in some systemically administered drugs. A greater AH drug level is expected to be achieved with intracameral administration than with topical application.(338)

4.2.2. Routes of Drug Delivery to the Posterior Eye

The ideal routes are the IVT and periocular routes. IVT injection is used due to its capacity to deliver drugs in close proximity to the target tissue.(19,339,340) In the recent past, the periocular route has also garnered immense popularity, as it minimizes the risk of endophthalmitis and retinal damage associated with the IVT route. For drug delivery to the posterior eye, this route is considered to be the most efficient and the least painful. However, drug washout is one of the major limitations associated with this route, as the drug is required to pass through static, dynamic, and metabolic barriers to attain a therapeutic level at the desired site of action.(341)

4.2.3. Systemic Route

Delivery of drugs through systemic route faces various challenges limiting its applicability. Drug transport from the systemic circulation to the retina is controlled by two blood–ocular barrier systems, including the blood–aqueous humor barrier and the blood–retinal barrier.(342) Epithelial or endothelial tight cellular junctions of the blood–ocular barrier restrict intraocular transport of hydrophilic drug substances. Extensive research in past few years has revealed that capillary endothelial cells of the blood–brain barrier and blood–retinal barrier are morphologically different.(343) Past research also revealed the presence of different influx and efflux transporters on the blood–retinal barrier that may modulate intraocular drug concentrations after systemic administration.(344) Clear understanding of these molecular mechanisms will open a new path for developing new strategies to treat retinal disorders after systemic drug administration.
It is important to mention that systemic administration of drugs can lead to ocular adverse effects, with a possibility of temporary visual disturbances and permanent vision loss. Thus, ophthalmic toxicities should be carefully monitored, and clinical practice guidelines should be strictly followed.(345) Administration of eye drops can also lead to unwanted systemic bioavailability, as the concentrations of active ingredients in medicinal preparations are high. As such, children are subject to a greater risk of such side effects due to their immature blood–brain barrier or their lack of ability to efficiently metabolize a drug. In this context, measures must be taken to monitor the serious side effects and reduce systemic absorption.(346) Other than this, oral administration of drugs, as exemplified by acetazolamide, may also lead to unwanted effects, such as malaise, fatigue, depression, weight loss, anorexia, and paresthesia.(347) To overcome these problem, different nanocarriers have been used to improve retinal drug bioavailability and to reduce the side effects after systemic administration. In this context, Kim et al. found that intravenous administration of gold nanoparticles was able to cross the blood–retinal barrier and showed lesser toxicity in retinal endothelial cells.(348)

4.3. Delivery Systems

Delivery systems have a key role in the transportation of drugs across the ocular tissues to enable the therapeutics reach specific tissues in the eye. Conventional dosage forms such as solutions, ointments, and suspensions are used for drug delivery to the anterior segment through the topical route.(349) However, these formulations have limited bioavailability and are often required to be administered frequently owing to their shorter duration of action. To overcome these limitations and improve ocular bioavailability, several studies have been conducted in this field. For the conventional dosage forms, the short contact time of eye drops on the surface of the eye can be extended based on the design of the formulation (e.g., gels, inserts, gelifying formulations, and others). For improving the bioavailability of drugs, the use of cyclodextrins has been recently employed as an effective approach in some studies. A suspension formulation of cilistazol, an antiglaucoma agent containing cyclodextrin with improved solubility as well as bioavailability, exemplifies the success of this strategy.(15) Increase in the contact time, reduction of nasolacrimal drainage, minimization of tear dilution, and attainment of higher effective concentrations are some of the advantages offered by ointments. The recently enhanced application of water-soluble bases (gels) is attributed to several benefits over petrolatum bases, such as better stability, spreadability, and low irritability.(350) This section presents the drug delivery systems that are currently being employed for ocular therapeutics.

4.3.1. Nanoparticles

Nanoparticles are colloidal drug carriers (10–1000 nm) that are considered to be quite versatile for ODD. The delivery properties of the NPs can be varied through modification of the size/charge and can be fine-tuned and adjusted to target the desired region of the eye.(351) Recent advances in nanotechnology clearly indicate its potential to overcome the limitations associated with the use of conventional DDS. An obvious benefit offered by nanoparticles is reductions in the sensation and irritation of the eye owing to their particle size. In addition, the main advantages of utilizing nanocarriers for ocular disease treatment are: (i) enhancement of the drug permeability across the blood–aqueous barrier and cornea, (ii) prolongment of the drug contact time with ocular tissues, (iii) facilitation of site-specific delivery of the drugs in a controlled manner, thereby minimizing the side-effects of the drug, (iv) protection of drugs from degradation leading to increased drug stability, and (v) sustainment of drug release and improvement of the therapeutic efficacy.(352)
Nevertheless, NPs still face some challenges, such as low drug loading and burst drug release. Furthermore, adequate attention must be made toward the assessment of the safety (toxicity) profile of the nanocarriers. Despite extensive investigations, only a few nanocarriers for the treatment of anterior segment diseases are undergoing clinical investigations. Taking this into consideration, it is suggested that higher numbers of clinical explorations are required to ensure their progress in the ODD field.

4.3.2. Liposomes

Liposomes have been significantly explored for the encapsulation of ocular therapeutics. Liposomes are particularly suitable for drugs with a low partition coefficient, high molecular weight, low solubility, and poor absorption. Liposomes are also considered as versatile nanocarriers for ODD, as their lipid composition, size, and charge can be modified. For example, a positively charged liposome demonstrated enhanced transcorneal flux of penicillin G (four-folds), thereby imparting enhanced permeability in the cornea.(353) In a recent investigation, cyclosporine A (CsA)-encapsulated liposomes were evaluated for their potential to treat DE syndrome. The results of the study revealed promising results attained with CsA-liposomes in terms of improved therapeutic efficacy and reduced ocular irritation in comparison to the nonliposome group.(353) In another study, 2–10-fold greater concentrations of the drug in the sclera, cornea, iris, lens, and vitreous humor were achieved by ganciclovir liposomes in comparison to ganciclovir solution.(354) Another notable example is Bevacizumab-loaded liposomes for IVT delivery (rabbit eyes) that demonstrated slower clearance when compared with the antibody solution and a higher drug concentration–time curve.(355) Taken together, liposomal formulations owing to improved contact with ocular tissues and the capacity to protect the drugs from metabolic enzymes exerts favorable effects on ODD.(356,357)

4.3.3. Niosomes

Niosomes are bilayered, nanosized vesicles (10–1000 nm in size) composed of biodegradable and biocompatible amphiphilic nonionic surfactants.(357,358) Owing to the chemical stability of vesicles that can accommodate both hydrophilic and lipophilic drugs coupled with the low toxicity of nonionic surfactants, niosomes are considered to be suitable carrier systems for targeted, sustained release of drugs and enhanced bioavailability.(359−361) The penetration-enhancing capacity of surfactants via removal of the mucus layer and breakage of junctional complexes might be responsible for the increase in the ocular bioavailability of water-soluble drugs entrapped in niosomes (Table 11).(362)
Table 11. Recent Developments of Niosomes for Ocular Drug Delivery
TypeResults
niosomal formulation of cyclopentolateThe formulation delivered the drug independent of the pH and demonstrated improvement in bioavailability(354)
timolol maleate-loaded niosomes and discomesTimolol maleate-loaded nisosomes and discomes for the treatment of OHTN were synthesized.
 It was observed that discomes entrapped more drug and led to increased ocular bioavailability in comparison to niosomes.(359)
         
mucoadhesive timolol maleate-loaded chitosan and Carbopol-coated nsiosomesMucoadhesive timolol maleate-loaded chitosan and Carbopol-coated niosomes were developed by a reversed-phase evaporation method.
 In vitro studies indicated that the formulation releases the drug in a sustained manner over a prolonged period.(360,361)
         
novel elastic niosomes (ethoniosomes)The ocular delivery of topical corticosteroids by ethoniosomes was evaluated.
 The results were quite optimistic as prepared ethoniosomes did not cause ocular irritation, and the bioavailability was found to be higher than the commercial products.
 Remarkably lower IOP elevation was achieved with ethoniosomes than with the commercial products.(362)
         
Gentamicin sulfate-loaded niosomesGentamicin sulfate-loaded niosomes composed of Tween 60, cholesterol and dicetyl phosphate can be used over a longer period of time when introduced into eye.
 In vitro studies indicated a high retention of the niosomal formulation compared to the drug solution and observed no irritation in albino rabbits.(363)

4.4. Recent Advances

The recent advances in delivery technologies are presented in Table 12. sections 4.5 and 4.6, cover the updates on Ozurdex and Bimatoprost. The list of sustained release systems in clinical development is presented in Table 13.
Table 12. Recent Advances in Ocular Drug Delivery
TechnologyDetails
sustained-release ocular delivery technologiesFour drugs with sustained release systems are FDA approved named commercially as Vitrasert, Retisert, Ozurdex, and Iluvien.(364,365)
         
punctum plugBiocompatible and noninvasive anterior segment ocular implants inserted into the tear ducts.
 Sustained and controlled drug release up to 180 days is attainable with punctum pug delivery system (PPDS).
 Recently smartplug developed a PPDS constructed from a thermosensitive hydrophobic acrylic polymer for dry eye disease.(16)
         
preservative-free multidose eye dropsMultidose bottles dispense drops employs a filtering system or a nonreturn valve, prohibiting the entry of bacteria.(365)
 The uniway valve system does not allow the contaminated liquid to re-enter the container after the disbursion of the dose which completely confiscate the requirement of filtering the liquid after use.
 Its future may rely on valve system owing to its efficacy and safe delivery of formulations.(366)
         
Ocusurf nanostructured emulsionOcusurf is made up of three parts:
 (A) Nanostructured cores in which aqueous nanodispersion of dissolved hydrophobic drug is entrapped.
 (B) Mucoadhesive inert polymeric aqueous phase which enhances residence time.
 (C) Amphiphilic self-assembled layer that renders the rapid absorption of drug.
 The ocusurf is composed in such a manner that its interaction and bioadhesion with mucosa of ocular surface leads to the melting of nanocore followed by drug release in the eye at 37 °C.
 Various drugs has been formulated using ocusurf delivery system namely loteprednol etabonate, 0.1%, fluticasone propionate, 0.1%, and others.(367)
         
technologies for sterile sustained-release injectablesMicroencapsulation is a complex and advanced process used for encapsulation of small and large molecules using biodegradable matrices that can lead to controlled release of drug.
 EmulTech has developed a unique emulsion technology called ET4ME to accomplish this distinctive process that helps in creating a uniform particle size in a microparticulate suspension.(22)
         
topical ocular ringThe development of noninvasive sustained therapy ocular ring made up of silicone is considered to be best in class treatment for major eye diseases.
 Bimatoprost ring is the first discovered product used to treat glaucoma and OHTN.
 To accomplish the application of ocular ring, first the eye size is measured after which the suitable ring is placed under the upper eye lid followed by placement under the lower lid. This system releases medication slowly for six months.
 The ring is comfortable, available in various sizes and possesses a durable effect and easily dispensed by the physician.
 It also possesses advantage of delivering two drugs together for a remarkable time period owing to its high surface area and high capacity for sustained release system.
 In future, ocular ring may replace eye drops for glaucoma treatment.(20)
         
micro intraocular implants and devicesThe design of these devices and implants is highly précised and consist of ultrathin hitherto strong microsized materials that should have the proficiency of lasting for several years in a warm and humid environment.
 Polypropylene glaucoma drain, pupil-expanding devices and silicone corneal drug delivery device are some of the examples of intraocular implants used to treat various ocular diseases.(17)
         
drug delivery using biodegradable silica matrixBecause of the inert nature of silica, it is compatible with a number of APIs and is employed to obtain various dosage forms.
 Recently, nonmesoporous, biodegradable silica matrix technology has been developed by DelSiTech in which drug is released from the matrix with the dissolution of silica in tissue.
 It is notable that the dissolution rate of silica matrix can be adjusted in such a manner that the drug release can be controlled the release of drug from days to months, even up to years.(368)
         
Opsisporin: a long-acting drug delivery approachOpsisoprin is a sustained release ocular therapy for uveitis that consists of immunosuppressor, cyclosporine which is encapsulated with bioresorbable polymer excipients in such a way that it gets entrapped in the polymer matrix.
 It is undergoing developmental phase by Midatech.(368)
         
polymeric micelles for ODDPolymeric micelles have proved their efficacy in DDS by improving the solubility and potential of hydrophobic drugs.
 Generally, these micelles consist of a hydrophobic core where hydrophobic drugs are encapsulated and another part called hydrophilic corona makes the formulation highly water-soluble.(369)
         
ODD nanowaferThe nanowafer is a mini circular disk made up of a transparent polymeric material enclosed with drug nanoreservoirs.
 This system can deliver a variety of drugs by simply instilling it on ocular surface by patient’s fingertip and there is no need of any clinical practice making this system a convenient mode of ODD.(370)
         
contact lensesOcular delivery of drugs using contact lenses is proved to be a promising method, has ability to deliver drug in posterior as well as anterior chamber through both the corneal route and the conjunctiva–sclera pathway.
 The contact lenses are classified into soft and rigid lenses on the basis of polymeric material used. The composition of the contact lenses decides the releasing pattern of drug, so lenses for drug delivery should be selected based on its specific clinical application.(18)
         
self-implantable double layered reservoirsSelf implantable double layered reservoirs are a kind of eye patch comprising micro drug reservoirs which is a multiple compartment model with benefit of releasing the same drug with dual kinetics.
 This system can also deliver different drugs consecutively to generate synergistic effect.
 As the name indicates the system is self-implantable, can be put in ocular tissue by gentle and brief pressing with help of thumb.
 This kind of delivery systems ensures simple home-based therapy for treating several ocular pathologies.(371)
         
InveltysUS FDA recently approved Inveltys (KPI-121 1%, Kala Pharmaceuticals) to treat postoperative inflammation and pain. It contains loteprednol etabonate (LE) 1% and is mechanized by technology known as mucus penetrating particles designed to increase loteprednol penetration across the mucus barrier, thereby enabling delivery of increased concentration of the drug to ocular tissue.(372)
         
intracanalicular insertDextenza is a FDA approved (November 30, 2018) dexamethasone ophthalmic (intracanalicular) insert developed by Ocular Therapeutix that can deliver the corticosteroid (for up to 30 days) to the ocular surface. It resorbs after the treatment and leaves nasolacrimal system.(373)

4.5. Ozurdex

Ozurdex is a biodegradable intravitreal implant that provides sustained release of dexamethasone (DEX) over a period of 6 months. It is composed of 0.7 or 0.35 mg of micronized DEX in an inactive biodegradable copolymer of polylactic-coglycolic acid.(374) Ozurdex received US FDA approval for the treatment of cystoid macular edema and posterior noninfectious uveitis in 2009.(375,376)
There are numerous lines of evidence indicating that central macular thickness and BCVA are improved by the use of Ozurdex.(377) Its efficacy was evaluated in naïve patients with DME, and it was found that BCVA was significantly improved in the study. Overall, it was concluded that meaningful functional and anatomical benefits were attained with sustained mid/long-term results.(378) Recently, a comparative study of the DEX implant with inferior fornix-based sub-Tenon triamcinolone injection (PSTA) was conducted. The investigation was carried in a total of 48 eyes that received DEX, whereas PSTA was received by 49 eyes. The results of the study demonstrated that a higher rate of disease control was achieved with DEX implantation in the initial 12 weeks postinjection.(379)
Other explorations on DEX implants have validated their efficacy in ocular diseases without significant ocular complications.(380,381) Recently, another study by a research group reported that the DEX implant exerted a transient reduction in endothelial cell density, with no change in the cell morphology observed in the injected eyes. The authors concluded that this could be due to some kind of chemical toxicity and that these effects should be given consideration while using the implant in compromised corneas prior to decision making.(382)
The consideration of intraocular steroid therapy as a second-line treatment is basically attributed to their unfavorable side effects profile, which involves elevated IOP and cataract formation.(383) However, Ozurdex has demonstrated favorable effects in this context, as the increase in IOP after Ozurdex is relatively lower than that observed with other steroids.(384) Recently, a study evaluated Ozurdex on IOP rise among different geographic populations, and the results demonstrated that Ozurdex caused higher increases in IOP in Latino and South Asian groups compared with a Caucasian population.(385)
At present, a combination of Ozurdex and Eylea for DME is recruiting subjects for a phase 4 clinical investigation (NCT03984110). Subjects are being recruited for phase 4 clinical investigation of Ozurdex in DME (NCT03475407) as well as recurrent Vogt–Koyanagi–Harada (VKH) disease posterior uveitis (NCT03971279).

4.6. Bimatoprost

Bimatoprost 0.03% ophthalmic solution is generally well-tolerated, cost-effective, and thermally stable among all prostaglandins. It was approved by the US FDA as an eye drop in 2001 for treating OAG and OHTN.(386)
Though bimatoprost is widely used as eye drops, it suffers from limitations such as short ocular drug resistance/short residence time and poor ocular bioavailability.(387−390) To address these problems, Xu et al. prepared bimatoprost-loaded microemulsion laden contact lenses to improve bimatoprost uptake. Subsequent evaluation results indicated a 2-fold increase in the uptake/loading of bimatoprost along with improvements in the release rate profiles, as evidenced by the in vitro bimatoprost release profiles of the microemulsion contact lenses. Moreover, a low burst release as well as improvement in the bimatoprost retention were also observed for microemulsion contact lenses in in vivo studies in rabbit tear fluid.(391)
Another study on drug delivery systems evaluated a novel sustained release bimatoprost-loaded nanovesicular-thermosensitive in situ gelling implant for subconjunctival delivery. The results revealed favorable outcomes, such as extended in vitro release of bimatoprost (80.23%) for 10 days and an extension of the IOP-lowering effect over 2 months with single subconjunctival injection of bimatoprost loaded nanovesicular-thermosensitive in situ gelling implant in rats. Moreover, no irritation, inflammation, or infection was observed in the study.(392)
Additionally, a biodegradable implant (Bimatoprost SR) was designed that employed a biodegradable Novadur (Allergan plc) platform to provide a slow release of bimatoprost over time.(393) In phase 1/2 clinical trials, it was found that Bimatoprost SR implant and bimatoprost administered topically (0.03%) induced similar IOP-lowering effects in humans.(394) Recently, it was also found that the topical bimatoprost could only exert IOP-lowering effects at high concentrations, whereas the IOP-lowering potential of Bimatoprost SR was dependent on the dose strength of the implant, as evidenced by the dose–response profiles. Additionally, Bimatoprost SR exerted higher IOP reductions than attained with topical dosing at the dose strengths of 60 μg and higher.(395) Further studies were conducted that revealed that Bimatoprost SR selectively delivered drug to the site of action (iris-ciliary body) and thus could lower the incidence of adverse events.(396)
The US FDA has recently accepted an NDA for Bimatoprost SR to reduce IOP in primary OAG or OHTN, as announced by Allergan. The application was filed on the basis of the results of phase 3 Artemis trials that demonstrated significant IOP reduction (30%) over 12 weeks with Bimatoprost SR. It was also observed that 80% of patients did not require further treatment for IOP control for at least 12 months after three treatments with Bimatoprost SR.(397)
Table 13. Sustained Release Systems in Clinical Development(398)
ImplantDetails
Latanoprost punctal plug delivery systemanterior segment implants
 condition: OAG
 clinical trial: phase 2 (NCT01037036, NCT02014142, NCT00820300)
         
Punctum Plug1. OTX-TP
 drug: Travoprost
 anterior segment ocular implants
 condition: ocular hypertension
 clinical trial: phase III (NCT02914509)
 2. OTX-DP
 drug: dexamethasone
 anterior segment ocular implants
 condition: chronic allergic conjunctivitis and inflammation after cataract surgery
 clinical trial: phase III (NCT02988882, NCT02736175)
 3. OTX-TP2 (Travopost PPDPS)
 drug: Travoprost
 anterior segment ocular implants
 condition: open angle glaucoma
 clinical trial: phase I (NCT01845038)
 4. OTX-TP (travoprost PPDS) for the controlled delivery of travopost for 90 days to treat ocular hypertension (Phase III clinical trial, NCT02914509)
         
DurasertLatanoprost ophthalmic implant
 drug: Latanoprost
 condition: ocular hypertension and glaucoma
 posterior segment ocular implants
         
Timolol, Bimatoprost ocular insertocular insert
 drug: Timolol, Bimatoprost
 study: dose-ranging study clinical trial phase II (NCT02358369)
         
Ozudexdrug: dexamethasone intravitreal implant (FDA Approved)
 posterior segment disorders
 condition: macular edema posterior uveitis
 development stage: launched
 clinical trial: phase 4 (NCT01427751)
         
Vitrasertdrug: Ganciclovir
 intravitreal implant
 posterior segment disorders
 condition: CMV retinitis
 development stage: launched
 clinical trial: phase 3 (NCT00000135)
Retisertdrug: fluocinolone acetonide
 intravitreal implant
 posterior segment disorders
 condition: posterior uveitis
 development stage: launched
 clinical trial: phase 3 (NCT00570830)
         
Dexycudrug: dexamethasone intraocular suspension
 posterior segment disorders
 condition: postoperative inflammation
 development stage: launched
 clinical trial: phase 3 (NCT02547623)
         
Renexusdrug: CNTF (NT-501)
 intravitreal implant
 posterior segment disorders
 condition: atrophic AMD
 clinical trial phase II/III, phase II (NCT03316300)
         
Chronijectdrug: bBetamethasone
 intravitreal implant
 posterior segment disorders
 condition: DME
 clinical trial: phase II/III (NCT01546402)
         
Iluviendrug: flucinolone acetonide
 intravitreal implant
 posterior segment disorders
 condition: posterior uveitis macular edema
 wet AMD
 clinical trial: phase III (NCT01304706)
 It is the most recent FDA approved intravitreal implant approved in 2014 and the first long-term acting treatment for DME.
         
Brimonidinedrug: Brimonidine
 intravitreal implant
 posterior segment disorders
 condition: dry AMD
 clinical trial: phase II (NCT02087085)
         
IBI-20089drug: triamcinolone acetonide
 IVT implant
 posterior segment disorders
 condition: wet AMD
 clinical trial: phase II (NCT01175395)
         
RETAACdrug: triamcinolone acetonide
 intravitreal implant
 posterior segment disorders
 condition: DME
 clinical trial: phase I/II (NCT00407849)
         
Cortijectdrug: dexamethasone
 intravitreal implant
 posterior segment disorders
 condition: DME
 clinical trial: phase I (NCT00665106)
         
NT-503release VEGF receptor Fc-fusion protein
 intravitreal implant
 posterior segment disorders
 condition: wet AMD
 clinical trial: phase I (NCT02228304)
         
AR-1105drug: dexamethasone
 intravitreal implant
 posterior segment disorders
 condition: macular edema
 clinical trial: phase II (NCT03739593)

6. Future Perspectives

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A substantial amount of research was conducted in ocular drug discovery field in the past decade. The FDA approvals of netarsudil, LBN ophthalmic solution (0.024%), and FDC [latanoprost (0.005%) and netarsudil (0.02%)] for glaucoma, brolucizumab for wet AMD, Luxturna for retinitis pigmentosa, Dexamethasone intracanalicular insert for ocular inflammation, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. Additionally, NO-donating PDE5 inhibitors, as well as the NO-donating sGC stimulators developed by Nicox (International Ophthalmic R&D Company), have garnered optimistic results, and it is quite hopeful that these NO donors might replicate similar success as that of the NO-donating latanoprost analogue (LBN, ophthalmic solution, 0.024%). In the context of AMD, gene therapy appears to be the future preferred therapy to achieve tissue repair and regeneration. At present, a number of gene therapies are undergoing clinical investigations for AMD, such as AdGVPEDF.11D, AVA 001 (AAVsFLt1), AAV2-SFLT01, ADVM-022, RGX-314, RetinoStat, and HMR59. Other than the clinical investigations, several structure–activity relationship studies have been conducted for ocular drug discovery. Specifically, these medicinal chemistry campaigns have focused on complement pathway inhibitors, ROCK inhibitors, CA inhibitors, RBP4 antagonists, VEGFR-2 inhibitors, and AR ligands, along with other chemical classes. A recent exploration in the field of cataract identified an oxysterol as a potential compound that improved lens transparency and holds enough promise to be investigated further. It is noteworthy to mention that the field of cataract faces a bigger challenge to enhance the uptake of cataract surgery (lens replacement) in rural areas, and appropriate measures need to be taken to reduce the cataract burden in the rural community. Overall, the clinical and preclinical pipelines of these agents are endowed with numerous small-molecule inhibitors with exciting potential. Numerous preliminary investigations have been conducted by medicinal chemists to design agents for the treatment of ocular diseases, employing rational drug design strategies. Regardless of the initial promise displayed by various chemical classes synthesized as a part of this preliminary investigation, an amplification of the preliminary results to the clinical level is required to ascertain conclusive benefits in the long run.
The expertise from formulation chemists is of the utmost importance to fabricate drug release platforms to optimize the delivery of either large biologics or small-molecule drugs and attain patient compliance, which is extremely critical for long-term therapeutic outcomes. To accomplish this goal, adequate attempts have been made to develop techniques that can provide prolonged action and increase the bioavailability of the drugs coupled with improving patient safety and minimizing side-effects. Overall, the findings covered in this perspective present recent advances in the field of ocular drug discovery. The present scenario makes it quite prudent that the development of new therapeutics for ocular diseases will require expertise from teams composed of chemists, biologists, and formulation experts.

Author Information

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  • Corresponding Authors
  • Authors
    • Kuei-Ju Cheng - School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, TaiwanDepartment of Pharmacy, Taipei Municipal Wanfang Hospital, Taipei Medical University, No. 111, Section 3, Xing-Long Road, Taipei 11696, Taiwan
    • Chien-Ming Hsieh - School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
  • Notes
    The authors declare no competing financial interest.

Biographies

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Kuei-Ju Cheng

Kuei-Ju Cheng received her PharmD from the University of Iowa (2003) and completed pharmacy residency in Valley Medical Center, Renton, Washington. She has 10 years experience in clinical pharmacy and vice director of the Department of Pharmacy of Taipei Municipal Wanfang Hospital (Managed by Taipei Medical University). Her research focuses on medication usage and safety in various diseases. She also has publications on the outcomes of pharmacist interventions with different strategies.

Chien-Ming Hsieh

Chien-Ming Hsieh received his Ph.D. in Pharmaceutical Science from King’s College London (2010) and obtained a postdoctoral fellowship at the Institute of Molecular Biology, Academia Sinica. Dr. Hsieh is currently Assistant Professor at School of Pharmacy, Taipei Medical University. His research focuses on improving the delivery of low molecular weight drugs and biomolecules. He has published 15 papers in peer-reviewed journals on a diverse range of topics in using nanoparticles as drug delivery systems both significant amounts of data as well as analytic advances.

Kunal Nepali

Kunal Nepali received a Doctoral Degree in Pharmaceutical Chemisty in the year 2012 from ISF College of Pharmacy, Moga, Punjab, India. After attaining four years of postdoctoral training from School of Pharmacy, Taipei Medical University, Taiwan, he joined the same department as an Assistant Professor. His scientific interests focus on the rational design and synthesis of small-molecule therapeutics.

Jing-Ping Liou

Jing-Ping Liou is currently working as a Professor of Medicinal Chemistry in School of Pharmacy, Taipei Medical University, Taiwan. He has extensive experience in the design and synthesis of small-molecule cancer therapeutics. His publication profile which includes more than 20 contributions to Journal of Medicinal Chemistry speaks volume of his contribution to the field of drug discovery. He works in tandem with the industrial sector in pursuit of developing novel clinical drug candidates. He received Ph.D. degree from the College of Medicine, National Taiwan University and obtained postdoctoral training from National Health Research Institutes.

Acknowledgments

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The corresponding authors are supported by grants from MOST, Taiwan (grant no. 107-2113-M-038-001 and MOST108-2320-B-038-010-MY2 (2-1). We are grateful to the Springer Nature and ACS Publications for permitting the inclusion of Figures 2, 5 and 8 in this Perspective.

Abbreviations Used
AMD

age-related macular degeneration

RGCs

retinal ganglion cells;

anti-VEGF

antivascular endothelial growth factor

RPE

retinal pigment epithelium

CNV

choroidal neovascularisation

iPS

pluripotent stem

RBP

retinol binding protein

RGC

retinal ganglion cell

IOP

intraocular pressure

MMPs

Matrix Metalloproteinases

ECM

extracellular matrix

MLC

myosin light-chain

NTG

normal-tension glaucoma

ROCK

Rho-associated coiled-coil protein kinase

AR

adenosine receptors

DR

diabetic retinopathy

DME

diabetic macular edema

BCVA

best-corrected visual acuity

IP

inflection points

NPs

nanoparticles

AP

alternative complement pathway

HIF

hypoxia-inducible factor

VAP-1

vascular adhesion protein-1

CFTR

cystic fibrosis transmembrane conductance regulator

mTOR

mammalian target of rapamycin

OAG

open angle glaucoma

OHTN

ocular hypertension/ocular hypertensive

LBN

latanoprostene bunod)

PEDF

pigment epithelium derived factor

sFLT-1

fms-like tyrosine kinase-1

ALT

argon laser trabeculoplasty

GLT

glaucoma laser trial

SLT

selective laser trabeculoplasty

FP

prostaglandin F receptor

LBN

latanoprostene bunod ophthalmic solution

NO

nitric oxide

LTN

latanoprostene

TIM

timalol

IOL

intraocular lens

CCT

conditional cash transfers

BC

Bruch’s choroid

sGC

soluble guanylate cyclase

DEX

dexamethasone

PSTA

fornix-based sub-Tenon triamcinolone injection

NDA

new drug application

TM

trabecular meshwork

AR

adenosine receptor

ERK

extracellular signal regulated kinases

PLC

phospholipase

CTGF

connective tissue growth factor

AAV

adenovirus-associated vector

FP

prostaglandin F

CA

carbonic anhydrase

cryAB

aBcrystallin

DSF

differential scanning fluorimetry

MST

microscale thermophoresis

VAP-1

vascular adhesion protein-1

PPDS

punctum pug delivery system

IRD

inherited retinal diseases

NOS

nitric oxide synthase

PDE5

phosphodiesterase-5

DEX

dexamethasone

sst2

somatostatin receptor subtype

TM

trabecular meshwork

IVT

intravitreal

TKI

tyrosine kinase inhibitors

DED

dry eye disease

ODD

ocular drug delivery

FDC

fixed dose combination

DE

dry eye

GA

geographic atrophy

AAV

adeno-associated virus

ONT

ocular normotensive

DDS

drug delivery systems

PPDS

punctum pug delivery system

DEX

dexamethasone

NOS

nitric oxide synthase

LBN

latanoprostene bunod

PDE5

phosphodiesterase-5 inhibitor

SAR

structure–activity relationship.

References

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This article references 398 other publications.

  1. 1
    (a) Graw, J. Eye development. Curr. Top. Dev. Biol. 2010, 90, 343386,  DOI: 10.1016/S0070-2153(10)90010-0 .
    (b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140146,  DOI: 10.1016/j.clindermatol.2014.10.006
  2. 2
    Awwad, S.; Mohamed Ahmed, A. H.; Sharma, G.; Heng, J. S.; Khaw, P. T.; Brocchini, S.; Lockwood, A. Principles of pharmacology in the eye. Br. J. Pharmacol. 2017, 174, 42054223,  DOI: 10.1111/bph.14024
  3. 3
    Clark, A. F.; Yorio, T. Ophthalmic drug discovery. Nat. Rev. Drug Discovery 2003, 2, 448459,  DOI: 10.1038/nrd1106
  4. 4
    Zhang, K.; Zhang, L.; Weinreb, R. N. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat. Rev. Drug Discovery 2012, 11, 541559,  DOI: 10.1038/nrd3745
  5. 5
    Zhang, J.; Tuo, J.; Wang, Z.; Zhu, A.; Machalińska, A.; Long, Q. Pathogenesis of common ocular diseases. J. Ophthalmol. 2015, 2015, 734527,  DOI: 10.1155/2015/734527
  6. 6
    Blindness and Vision Impairment; World Health Organization, 2019; https://www.who.int/blindness/en/ (accessed 2019-03-29).
  7. 7
    Sturdivant, J. M.; Royalty, S. M.; Lin, C. W.; Moore, L. A.; Yingling, J. D.; Laethem, C. L.; Sherman, B.; Heintzelman, G. R.; Kopczynski, C. C.; deLong, M. A. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett. 2016, 26, 24752480,  DOI: 10.1016/j.bmcl.2016.03.104
  8. 8
    Impagnatiello, F.; Bastia, E.; Almirante, N.; Brambilla, S.; Duquesroix, B.; Kothe, A. C.; Bergamini, M. V. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br. J. Pharmacol. 2019, 176, 10791089,  DOI: 10.1111/bph.14328
  9. 9
    Abidi, A.; Shukla, P.; Ahmad, A. Lifitegrast: a novel drug for treatment of dry eye disease. J. Pharmacol. Pharmacother. 2016, 7, 194198,  DOI: 10.4103/0976-500X.195920
  10. 10
    Mehran, N. A.; Sinha, S.; Razeghinejad, R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost. Eye 2020, 34, 7288,  DOI: 10.1038/s41433-019-0671-0
  11. 11
    Lewis, R. A.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339344,  DOI: 10.1136/bjophthalmol-2015-306778
  12. 12
    Patel, U.; Boucher, M.; de Léséleuc, L.; Visintini, S. Voretigene neparvovec: an emerging gene therapy for the treatment of inherited blindness. CADTH Issues in Emerging Health Technologies 2018, 169, 311
  13. 13
    ReSure Sealant; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/resure-sealant/ (accessed 2020-03-05).
  14. 14
    Dugel, P. U.; Koh, A.; Ogura, Y.; Jaffe, G. J.; Schmidt-Erfurth, U.; Brown, D. M.; Gomes, A. V.; Warburton, J.; Weichselberger, A.; Holz, F. G. Hawk and harrier: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2020, 127, 7284,  DOI: 10.1016/j.ophtha.2019.04.017
  15. 15
    (a) Khan, S.; Warade, S.; Singhavi, D. J. Improvement in ocular bioavailability and prolonged delivery of tobramycin sulfate following topical ophthalmic administration of drug-loaded mucoadhesive microparticles incorporated in thermosensitive in situ gel. J. Ocul. Pharmacol. Ther. 2018, 34, 287297,  DOI: 10.1089/jop.2017.0079 .
    (b) Garty, S.; Shirakawa, R.; Warsen, A.; Anderson, E. M.; Noble, M. L.; Bryers, J. D.; Ratner, B. D.; Shen, T. T. Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgery. Invest. Ophthalmol. Visual Sci. 2011, 52, 61096116,  DOI: 10.1167/iovs.10-6071 .
    (c) Foureaux, G.; Franca, J. R.; Nogueira, J. C.; de Oliveira Fulgencio, G.; Ribeiro, T. G.; Castilho, R. O.; Yoshida, M. I.; Fuscaldi, L. L.; Fernandes, S. O.; Cardoso, V. N.; Cronemberger, S.; Faraco, A. A.; Ferreira, A. J. Ocular inserts for sustained release of the angiotensin-converting enzyme 2 activator, diminazene aceturate, to treat glaucoma in rats. PLoS One 2015, 10, e0133149,  DOI: 10.1371/journal.pone.0133149 .
    (d) Khurana, G.; Arora, S.; Pawar, P. K. Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluations. Int. J. Pharm. Invest. 2012, 2, 7077,  DOI: 10.4103/2230-973X.100040 .
    (e) Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423430,  DOI: 10.5650/jos.59.423 .
    (f) Sieg, J. W.; Robinson, J. R. Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments. J. Pharm. Sci. 1979, 68, 724728,  DOI: 10.1002/jps.2600680619 .
    (g) Newton, D. W.; Becker, C. H.; Torosian, G. Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic use. J. Pharm. Sci. 1973, 62 (9), 15381542,  DOI: 10.1002/jps.2600620936 .
    (h) Ludwig, A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Delivery Rev. 2005, 57, 15951639,  DOI: 10.1016/j.addr.2005.07.005
  16. 16
    Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602624,  DOI: 10.1124/jpet.119.256933
  17. 17
    (a) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. P. Silica xerogel as an implantable carrier for controlled drug delivery-evaluation of drug distribution and tissue effects after implantation. Biomaterials 2000, 21, 193198,  DOI: 10.1016/S0142-9612(99)00148-9 .
    (b) Jokinen, M.; Koskinen, M.; Areva, S. Rationale of using conventional sol-gel derived SiO2 for delivery of biologically active agents. Key Eng. Mater. 2008, 377, 195210,  DOI: 10.4028/www.scientific.net/KEM.377.195
  18. 18
    (a) Phan, C. M.; Subbaraman, L. N.; Jones, L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye Contact Lens 2013, 39, 162168,  DOI: 10.1097/ICL.0b013e31827a7a07 .
    (b) Peng, C. C.; Kim, J. A.; Chauhan, A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials 2010, 31, 40324047,  DOI: 10.1016/j.biomaterials.2010.01.113
  19. 19
    Bochot, A.; Fattal, E. Liposomes for intravitreal drug delivery: a state of the art. J. Controlled Release 2012, 161, 628634,  DOI: 10.1016/j.jconrel.2012.01.019
  20. 20
    Hong, C. H.; Arosemena, A.; Zurakowski, D.; Ayyala, R. S. Glaucoma drainage devices: a systematic literature review and current controversies. Surv. Ophthalmol. 2005, 50, 4860,  DOI: 10.1016/j.survophthal.2004.10.006
  21. 21
    Tseng, C. L.; Chen, K. H.; Su, W. Y.; Lee, Y. H.; Wu, C. C.; Lin, F. H. Cationic gelatin nanoparticles for drug delivery to the ocular surface: in vitro and in vivo evaluation. J. Nano. 2013, 2013, 238351,  DOI: 10.1155/2013/238351
  22. 22
    Ophthalmic Drug Delivery; Frederick Furness Publishing Ltd: Lewes, UK, 2019; https://www.ondrugdelivery.com/publications/63/ForSight.pdf/ (accessed 2019-01-24).
  23. 23
    Nocentini, A.; Ceruso, M.; Bua, S.; Lomelino, C. L.; Andring, J. T.; McKenna, R.; Lanzi, C.; Sgambellone, S.; Pecori, R.; Matucci, R.; Filippi, L.; Gratteri, P.; Carta, F.; Masini, E.; Selleri, S.; Supuran, C. T. Discovery of β-adrenergic receptors blocker-carbonic anhydrase inhibitor hybrids for multitargeted antiglaucoma therapy. J. Med. Chem. 2018, 61, 53805394,  DOI: 10.1021/acs.jmedchem.8b00625
  24. 24
    Cioffi, C. L.; Racz, B.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Dobri, N.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Bicyclic [3.3. 0]-octahydrocyclopenta [c] pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2015, 58, 58635888,  DOI: 10.1021/acs.jmedchem.5b00423
  25. 25
    Uddin, M. I.; Evans, S. M.; Craft, J. R.; Marnett, L. J.; Uddin, M. J.; Jayagopal, A. Applications of azo-based probes for imaging retinal hypoxia. ACS Med. Chem. Lett. 2015, 6, 445449,  DOI: 10.1021/ml5005206
  26. 26
    Maibaum, J.; Liao, S. M.; Vulpetti, A.; Ostermann, N.; Randl, S.; Rüdisser, S.; Lorthiois, E.; Erbel, P.; Kinzel, B.; Kolb, F.; Barbieri, S.; Wagner, J.; Durand, C.; Fettis, K.; Dussauge, S.; Hughes, N.; Delgado, O.; Hommel, U.; Gould, T.; Mac Sweeney, A.; Gerhartz, B.; Cumin, F.; Flohr, S.; Schubart, A.; Jaffee, B.; Harrison, R.; Risitano, A. M.; Eder, J.; Anderson, K. A small-molecule factor D inhibitors targeting the alternative complement pathway. Nat. Chem. Biol. 2016, 12, 11051110,  DOI: 10.1038/nchembio.2208
  27. 27
    Vulpetti, A.; Randl, S.; Rudisser, S.; Ostermann, N.; Erbel, P.; Mac Sweeney, A.; Zoller, T.; Salem, B.; Gerhartz, B.; Cumin, F.; Hommel, U.; Dalvit, C.; Lorthiois, E.; Maibaum, J. Structure-based library design and fragment screening for the identification of reversible complement factor D protease inhibitors. J. Med. Chem. 2017, 60, 19461958,  DOI: 10.1021/acs.jmedchem.6b01684
  28. 28
    Lorthiois, E.; Anderson, K.; Vulpetti, A.; Rogel, O.; Cumin, F.; Ostermann, N.; Steinbacher, S.; Mac Sweeney, A.; Delgado, O.; Liao, S.-M.; Randl, S.; Rüdisser, S.; Dussauge, S.; Fettis, K.; Kieffer, L.; de Erkenez, A.; Yang, L.; Hartwieg, C.; Argikar, U. A.; La Bonte, L. R.; Newton, R.; Kansara, V.; Flohr, S.; Hommel, U.; Jaffee, B.; Maibaum, J. Discovery of highly potent and selective small-molecule reversible factor D inhibitors demonstrating alternative complement pathway inhibition in vivo. J. Med. Chem. 2017, 60, 57175735,  DOI: 10.1021/acs.jmedchem.7b00425
  29. 29
    Jendza, K.; Kato, M.; Salcius, M.; Srinivas, H.; De Erkenez, A.; Nguyen, A.; McLaughlin, D.; Be, C.; Wiesmann, C.; Murphy, J.; Bolduc, P.; Mogi, M.; Duca, J.; Namil, A.; Capparelli, M.; Darsigny, V.; Meredith, E.; Tichkule, R.; Ferrara, L.; Heyder, J.; Liu, F.; Horton, P. A.; Romanowski, M. J.; Schirle, M.; Mainolfi, N.; Anderson, K.; Michaud, G. A. A small-molecule inhibitor of C5 complement protein. Nat. Chem. Biol. 2019, 15, 666668,  DOI: 10.1038/s41589-019-0303-9
  30. 30
    Karki, R.; Powers, J.; Mainolfi, N.; Anderson, K.; Belanger, D. B.; Liu, D.; Ji, N.; Jendza, K.; Gelin, C. F.; Mac Sweeney, A.; Solovay, C.; Delgado, O.; Crowley, M.; Liao, S. M.; Argikar, U. A.; Flohr, S.; La Bonte, L. R.; Lorthiois, E. L.; Vulpetti, A.; Brown, A.; Long, D.; Prentiss, M.; Gradoux, N.; de Erkenez, A.; Cumin, F.; Adams, C.; Jaffee, B.; Mogi, M. Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway. J. Med. Chem. 2019, 62, 46564668,  DOI: 10.1021/acs.jmedchem.9b00271
  31. 31
    Haddad, S.; Chen, C. A.; Santangelo, S. L.; Seddon, J. M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 2006, 51, 316363,  DOI: 10.1016/j.survophthal.2006.05.001
  32. 32
    Rattner, A.; Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nat. Rev. Neurosci. 2006, 7, 860872,  DOI: 10.1038/nrn2007
  33. 33
    Chou, R.; Dana, T.; Bougatsos, C.; Grusing, S.; Blazina, I. Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016, 315, 915933,  DOI: 10.1001/jama.2016.0783
  34. 34
    Leibowitz, H. M.; Krueger, D. E.; Maunder, L. R.; Milton, R. C.; Kini, M. M.; Kahn, H. A.; Nickerson, R. J.; Pool, J.; Colton, T. L.; Ganley, J. I.; Loewenstein, T. R. The framingham eye study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973 −1975. Surv. Ophthalmol. 1980, 24, 335610,  DOI: 10.1016/0039-6257(80)90015-6
  35. 35
    Wong, W. L.; Su, X.; Li, X.; Cheung, C. M.; Klein, R.; Cheng, C. Y.; Wong, T. Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e10616,  DOI: 10.1016/S2214-109X(13)70145-1
  36. 36
    Maller, J.; George, S.; Purcell, S.; Fagerness, J.; Altshuler, D.; Daly, M. J.; Seddon, J. M. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 2006, 38, 10551059,  DOI: 10.1038/ng1873
  37. 37
    Klein, M. L.; Schultz, D. W.; Edwards, A.; Matise, T. C.; Rust, K.; Berselli, C. B.; Trzupek, K.; Weleber, R. G.; Ott, J.; Wirtz, M. K.; Acott, T. S. Age-related macular degeneration. clinical features in a large family and linkage to chromosome 1q. Arch. Ophthalmol. 1998, 116, 10821088,  DOI: 10.1001/archopht.116.8.1082
  38. 38
    Mitchell, P.; Wang, J. J.; Smith, W.; Leeder, S. R. Smoking and the 5-year incidence of age-related maculopathy: the blue mountains eye study. Arch. Ophthalmol. 2002, 120, 13571363,  DOI: 10.1001/archopht.120.10.1357
  39. 39
    Mitchell, P.; Liew, G.; Gopinath, B.; Wong, T. Y. Age-related macular degeneration. Lancet 2018, 392, 11471159,  DOI: 10.1016/S0140-6736(18)31550-2
  40. 40
    Crabb, J. W.; Miyagi, M.; Gu, X.; Shadrach, K.; West, K. A.; Sakaguchi, H.; Kamei, M.; Hasan, A.; Yan, L.; Rayborn, M. E.; Salomon, R. G.; Hollyfield, J. G. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1468214687,  DOI: 10.1073/pnas.222551899
  41. 41
    (a) Okubo, A.; Rosa, R. H.; Bunce, C. V.; Alexander, R. A.; Fan, J. T.; Bird, A. C.; Luthert, P. J. The relationships of age changes in retinal pigment epithelium and bruch’s membrane. Invest. Ophthalmol. Vis. Sci. 1999, 40, 443449.
    (b) Green, W. R.; McDonnell, P. J.; Yeo, J. H. Pathologic features of senile macular degeneration. Ophthalmology 1985, 92, 615627,  DOI: 10.1016/S0161-6420(85)33993-3
  42. 42
    Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat. Med. 2010, 16, 11071111,  DOI: 10.1038/nm1010-1107
  43. 43
    (a) Macular Degeneration Treatments; American Macular Degeneration Foundation: Northampton, MA. 2019; https://www.macular.org/treatments/ (accessed 2019-05-15).
    (b) Anti-VEGF Treatment; Royal National Institute of Blind People: London, 2019; https://www.rnib.org.uk/eye-health/eye-conditions/anti-vegf-treatment/ (accessed 2019-01-15).
  44. 44
    (a) Martin, D. F.; Maguire, M. G.; Ying, G. S.; Grunwald, J. E.; Fine, S. L.; Jaffe, G. J. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2011, 364, 18971908,  DOI: 10.1056/NEJMoa1102673 .
    (b) Aflibercept; DrugBank, 2019; https://www.drugbank.ca/drugs/DB08885/ (accessed 2019-01-17).
  45. 45
    Williams, M. A.; McKay, G. J.; Chakravarthy, U. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst. Rev. 2014, 15, CD009300,  DOI: 10.1002/14651858.CD009300.pub2
  46. 46
    Khandhadia, S.; Cipriani, V.; Yates, J. R.; Lotery, A. J. Age-related macular degeneration and the complement system. Immunobiology 2012, 217, 127146,  DOI: 10.1016/j.imbio.2011.07.019
  47. 47
    (a) Katz, M. L.; Robison, W. G. What is lipofuscin? defining characteristics and differentiation from other autofluorescent lysosomal storage bodies. Arch. Gerontol. Geriatr. 2002, 34, 169184,  DOI: 10.1016/S0167-4943(02)00005-5 .
    (b) Lamb, L. E.; Simon, J. D. A2E: a component of ocular lipofuscin. Photochem. Photobiol. 2004, 79, 127136,  DOI: 10.1111/j.1751-1097.2004.tb00002.x .
    (c) Iriyama, A.; Inoue, Y.; Takahashi, H.; Tamaki, Y.; Jang, W. D.; Yanagi, Y. A2E, a component of lipofuscin, is pro-angiogenic in vivo. J. Cell. Physiol. 2009, 220, 469475,  DOI: 10.1002/jcp.21792
  48. 48
    (a) Kanai, M.; Raz, A.; Goodman, D. S. Retinol-binding protein: the transport protein for vitamin A in human plasma. J. Clin. Invest. 1968, 47, 20252044,  DOI: 10.1172/JCI105889 .
    (b) Naylor, H. M.; Newcomer, M. E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 1999, 38, 26472653,  DOI: 10.1021/bi982291i
  49. 49
    Hussain, R. M.; Gregori, N. Z.; Ciulla, T. A.; Lam, B. L. Pharmacotherapy of retinal disease with visual cycle modulators. Expert Opin. Pharmacother. 2018, 19, 471481,  DOI: 10.1080/14656566.2018.1448060
  50. 50
    (a) Johnson, S. C.; Rabinovitch, P. S.; Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493, 338345,  DOI: 10.1038/nature11861 .
    (b) Park, T. K.; Lee, S. H.; Choi, J. S.; Nah, S. K.; Kim, H. J.; Park, H. Y.; Lee, H.; Lee, S. H. S.; Park, K. Adeno-associated viral vector-mediated mTOR inhibition by short hairpin RNA suppresses laser-induced choroidal neovascularization. Mol. Ther.--Nucleic Acids 2017, 8, 2635,  DOI: 10.1016/j.omtn.2017.05.012
  51. 51
    Singh, M. S.; MacLaren, R. E. Stem cell treatment for age-related macular degeneration: the challenges. Invest. Ophthalmol. Visual Sci. 2018, 59, AMD78AMD82,  DOI: 10.1167/iovs.18-24426
  52. 52
    Macular Degeneration; International Society for Stem Cell Research. 2019; https://www.closerlookatstemcells.org/stem-cells-medicine/macular-degeneration/ (accessed 2019-03-17).
  53. 53
    Villanueva, M. T. A stem-cell-derived eye patch for macular degeneration. Nat. Rev. Drug Discovery 2019, 18, 172,  DOI: 10.1038/d41573-019-00017-8
  54. 54
    Moore, N. A.; Bracha, P.; Hussain, R. M.; Morral, N.; Ciulla, T. A. Gene therapy for age-related macular degeneration. Expert Opin. Biol. Ther. 2017, 17, 12351244,  DOI: 10.1080/14712598.2017.1356817
  55. 55
    Bainbridge, J. W.; Smith, A. J.; Barker, S. S.; Robbie, S.; Henderson, R.; Balaggan, K.; Viswanathan, A.; Holder, G. E.; Stockman, A.; Tyler, N.; Petersen-Jones, S.; Bhattacharya, S. S.; Thrasher, A. J.; Fitzke, F. W.; Carter, B. J.; Rubin, G. S.; Moore, A. T.; Ali, R. R. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 2008, 358, 22312239,  DOI: 10.1056/NEJMoa0802268
  56. 56
    European Commission Approves Spark Therapeutics; Spark Therapeutics, 2019; http://ir.sparktx.com/news-releases/news-release-details/european-commission-approves-spark-therapeutics-luxturnar/ (accessed 2019-03-19).
  57. 57
    Gordon, K.; Del Medico, A.; Sander, I.; Kumar, A.; Hamad, B. Gene therapies in ophthalmic disease. Nat. Rev. Drug Discovery 2019, 18, 415416,  DOI: 10.1038/d41573-018-00016-1
  58. 58
    Constable, I. J.; Lai, C. M.; Magno, A. L.; French, M. A.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Degli-Esposti, M. A.; Rakoczy, E. P. Gene therapy in neovascular age-related macular degeneration: three-year follow-up of a phase 1 randomized dose escalation trial. Am. J. Ophthalmol. 2017, 177, 150158,  DOI: 10.1016/j.ajo.2017.02.018
  59. 59
    Bordet, T.; Behar-Cohen, F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discovery Today 2019, 24, 16851693,  DOI: 10.1016/j.drudis.2019.05.038
  60. 60
    Campochiaro, P. A.; Nguyen, Q. D.; Shah, S. M.; Klein, M. L.; Holz, E.; Frank, R. N.; Saperstein, D. A.; Gupta, A.; Stout, J. T.; Macko, J.; DiBartolomeo, R.; Wei, L. L. Adenoviral vector delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum. Gene Ther. 2006, 17, 167176,  DOI: 10.1089/hum.2006.17.167
  61. 61
    Rakoczy, E. P.; Lai, C. M.; Magno, A. L.; Wikstrom, M. E.; French, M. A.; Pierce, C. M.; Schwartz, S. D.; Blumenkranz, M. S.; Chalberg, T. W.; Degli-Esposti, M. A.; Constable, I. J. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1-year follow-up of a phase 1 randomised clinical trial. Lancet 2015, 386, 23952403,  DOI: 10.1016/S0140-6736(15)00345-1
  62. 62
    Avalanche Biotechnologies, Inc., Announces Positive Top-Line Phase 2a Results for Ava-101 in Wet Age-Related Macular Degeneration; Adverum Biotechnologies, 2019; http://investors.adverum.com/news-releases/newsrelease-details/avalanche-biotechnologies-inc-announces-positivetop-line-phase/ (accessed 2019-12-10).
  63. 63
    Constable, I. J.; Pierce, C. M.; Lai, C. M.; Magno, A. L.; Degli-Esposti, M. A.; French, M. A.; McAllister, I. A.; Butler, S.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Rakoczy, E. P. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine 2016, 14, 168175,  DOI: 10.1016/j.ebiom.2016.11.016
  64. 64
    Scaria, A. L.; LeHalpere, A.; Purvis, A.; delacono, C.; Cheng, S.; Wadsworth, S.; Campochiaro, P.; Heier, J.; Buggage, R. Preliminary results of a phase 1, open-label, safety and tolerability study of a single intravitreal injection of AAV2-sFLT01 in patients with neovascular age-related macular degeneration. Mol. Ther. 2016, 24, S98,  DOI: 10.1016/S1525-0016(16)33058-1
  65. 65
    Heier, J. S.; Kherani, S.; Desai, S.; Dugel, P.; Kaushal, S.; Cheng, S. H.; Delacono, C.; Purvis, A.; Richards, S.; Le-Halpere, A.; Connelly, J.; Wadsworth, S. C.; Varona, R.; Buggage, R.; Scaria, A.; Campochiaro, P. A. Intravitreous injection of AAV2- sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017, 390, 5061,  DOI: 10.1016/S0140-6736(17)30979-0
  66. 66
    Regenxbio Programs; REGENXBIO: Rockville, MD, 2020; http://ir.regenxbio.com/news-releases/news-release-details/regenxbio-reports-continued-progress-across-programs-year-end-0/ (accessed 2019-12-14).
  67. 67
    Campochiaro, P. A.; Lauer, A. K.; Sohn, E. H.; Mir, T. A.; Naylor, S.; Anderton, M. C.; Kelleher, M.; Harrop, R.; Ellis, S.; Mitrophanous, K. A. Lentiviral vector gene transfer of endostatin/ Angiostatin for macular degeneration (GEM) study. Hum. Gene Ther. 2017, 28, 99111,  DOI: 10.1089/hum.2016.117
  68. 68
    ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2020; https://clinicaltrials.gov/ (accessed 2020-01-10).
  69. 69
    Update on Clinical Trials for Macular Degeneration; BrightFocus Foundation: Clarksburg, MD, 2019; https://www.brightfocus.org/macular/article/update-clinical-trials-macular/ (accessed 2010-03-09).
  70. 70
    Graybug Vision Initiates Phase 1/2 Trial of GB-102 for Wet Age-related Macular Degeneration; Graybug Vision, Inc.: Redwood City, CA, 2017; https://graybug.com/graybug-vision-initiates-phase-12-trial-of-gb-102-for-wet-age-related-macular-degeneration/ (accessed 2019-02-21).
  71. 71
    An Oral Drug for Treatment of AMD?; Bryn Mawr Communications LLC: Wayne, PA, 2019; http://retinatoday.com/2016/08/an-oral-drug-for-treatment-of-amd/ (accessed 2019-02-21).
  72. 72
    X-82 to Treat Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02348359/ (accessed Jan 30, 2019).
  73. 73
    Joussen, A. M.; Wolf, S.; Kaiser, P. K.; Boyer, D.; Schmelter, T.; Sandbrink, R.; Zeitz, O.; Deeg, G.; Richter, A.; Zimmermann, T.; Hoechel, J.; Buetehorn, U.; Schmitt, W.; Stemper, B.; Boettger, M. K. The developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial. Br. J. Clin. Pharmacol. 2019, 85, 347355,  DOI: 10.1111/bcp.13794
  74. 74
    Abicipar; Molecular Partners, 2019; https://www.molecularpartners.com/our-products/abicipar/ (accessed 2019-01-13).
  75. 75
    OPT 302; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800043497 (accessed 2019-02-19).
  76. 76
    Jaffe, G. J.; Ciulla, T. A.; Ciardella, A. P.; Devin, F.; Dugel, P. U.; Eandi, C. M.; Masonson, H.; Monés, J.; Pearlman, J. A.; Quaranta-El Maftouhi, M.; Ricci, F.; Westby, K.; Patel, S. C. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 2017, 124, 224234,  DOI: 10.1016/j.ophtha.2016.10.010
  77. 77
    Rosenfeld, P. J.; Feuer, W. J. Lessons from recent phase III trial failures: don’t design phase III trials Based on retrospective subgroup analyses from phase II trials. Ophthalmology 2018, 125, 14881491,  DOI: 10.1016/j.ophtha.2018.06.002
  78. 78
    Ophthotech Announces Results from Third Phase 3 Trial of Fovista in Wet Age-Related Macular Degeneration; Ophthotech, 2018; https://investors.ivericbio.com/news-releases/news-release-details/ophthotech-announces-results-third-phase-3-trial-fovistar-wet/ (accessed 2018-05-26).
  79. 79
    Papadopoulos, K. P.; Kelley, R. K.; Tolcher, A. W.; Razak, A. R.; Van Loon, K.; Patnaik, A.; Bedard, P. L.; Alfaro, A. A.; Beeram, M.; Adriaens, L.; Brownstein, C. M.; Lowy, I.; Kostic, A.; Trail, P. A.; Gao, B.; DiCioccio, A. T.; Siu, L. L. A phase I first-in-human study of nesvacumab (REGN910), a fully human anti-angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 2016, 22, 13481355,  DOI: 10.1158/1078-0432.CCR-15-1221
  80. 80
    Regula, J. T.; Lundh Von Leithner, P.; Foxton, R.; Barathi, V. A.; Cheung, C. M.; Bo Tun, S. B.; Wey, Y. S.; Iwata, D.; Dostalek, M.; Moelleken, J.; Stubenrauch, K. G.; Nogoceke, E.; Widmer, G.; Strassburger, P.; Koss, M. J.; Klein, C.; Shima, D. T.; Hartmann, G. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 2016, 8, 12651288,  DOI: 10.15252/emmm.201505889
  81. 81
    Risitano, A. M.; Storek, M.; Sahelijo, L.; Doyle, M.; Dai, Y.; Weitz, I.; Marsh, J. C. W.; Elebute, M.; O’Connell, C. L.; Kulasekararaj, A. G.; Ramsingh, G.; Marotta, S.; Hellmann, A.; Lundberg, A. S. Safety and pharmacokinetics of the complement inhibitor TT30 in a phase I trial for untreated PNH patients. Blood 2015, 126, 2137,  DOI: 10.1182/blood.V126.23.2137.2137
  82. 82
    Kassa, E.; Ciulla, T. A.; Hussain, R. M.; Dugel, P. U. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin. Biol. Ther. 2019, 19, 335342,  DOI: 10.1080/14712598.2019.1575358
  83. 83
    Yehoshua, Z.; de Amorim Garcia Filho, C. A.; Nunes, R. P.; Gregori, G.; Penha, F. M.; Moshfeghi, A. A.; Zhang, K.; Sadda, S.; Feuer, W.; Rosenfeld, P. J. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the complete study. Ophthalmology 2014, 121, 693701,  DOI: 10.1016/j.ophtha.2013.09.044
  84. 84
    Cousins, S. W. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a phase 1 study. Invest. Ophthalmol. Vis. Sci. 2010, 51, e-Abstract 1251. 1251
  85. 85
    Lampalizumab—Genentech; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800024383 (accessed 2019-01-15).
  86. 86
    Tesidolumab—MorphoSys; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800032650 (accessed Jan 17, 2019).
  87. 87
    Cheng, W. S.; Lu, D.; Chiang, C. H.; Chang, C. J. Overview of clinical trials for dry age-related macular degeneration. Yixue Yanjiu 2017, 37, 121129,  DOI: 10.4103/jmedsci.jmedsci_115_16
  88. 88
    Kubota, R.; Boman, N.; David, R.; Mallikaarjun, S.; Patil, S.; Birch, D. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator Article. Retina 2012, 32, 183188,  DOI: 10.1097/IAE.0b013e318217369e
  89. 89
    Holz, F. G.; Strauss, E. C.; Schmitz-Valckenberg, S.; van Lookeren Campagne, M. Geographic atrophy clinical features and potential therapeutic approaches. Ophthalmology 2014, 121, 10791091,  DOI: 10.1016/j.ophtha.2013.11.023
  90. 90
    Hanus, J.; Zhao, F.; Wang, S. Current therapeutic development for atrophic age-related macular degeneration. Br. J. Ophthalmol. 2016, 100, 122127,  DOI: 10.1136/bjophthalmol-2015-306972
  91. 91
    Motani, A.; Wang, Z.; Conn, M.; Siegler, K.; Zhang, Y.; Liu, Q.; Johnstone, S.; Xu, H.; Thibault, S.; Wang, Y.; Fan, P.; Connors, R.; Le, H.; Xu, G.; Walker, N.; Shan, B.; Coward, P. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J. Biol. Chem. 2009, 284, 76737680,  DOI: 10.1074/jbc.M809654200
  92. 92
    Zahn, G.; Vossmeyer, D.; Stragies, R.; Wills, M.; Wong, C. G.; Löffler, K. U.; Adamis, A. P.; Knolle, J. Preclinical evaluation of the novel small-molecule integrin inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch. Ophthalmol. 2009, 127, 13291335,  DOI: 10.1001/archophthalmol.2009.265
  93. 93
    Kuwada, S. K. Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr. Opin. Mol. Ther. 2007, 9, 9298
  94. 94
    Sonepcizumab—Lpath;Adis International Ltd. 2018; https://adisinsight.springer.com/drugs/800024045 (accessed 2018-12-29).
  95. 95
    Ibrahim, M. A.; Do, D. V.; Sepah, Y. J.; Shah, S. M.; Van Anden, E.; Hafiz, G.; Donahue, J. K.; Rivers, R.; Balkissoon, J.; Handa, J. T.; Campochiaro, P. A.; Nguyen, Q. D. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol. Toxicol. 2013, 14, 7,  DOI: 10.1186/2050-6511-14-7
  96. 96
    Taskintuna, I.; Abdalla Elsayed, M. E. A.; Schatz, P. Update on clinical trials in dry age related macular degeneration. Middle East Afr. J. Ophthalmol. 2016, 23, 1326,  DOI: 10.4103/0974-9233.173134
  97. 97
    Trimetazidine; DrugBank, 2019; https://www.drugbank.ca/drugs/DB09069/ (accessed May 12, 2019).
  98. 98
    Chiou, G. Is dry AMD treatable? a new ophthalmic solution may halt disease progression. Retina Today 2012, (May/June), 6971
  99. 99
    Jaffe, G. J.; Tao, W. A. A phase 2 study of encapsulated CNTF-secreting cell implant (NT-501) in patients with geographic atrophy associated with dry AMD-18-month. Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2005, Fort Lauderdale, FL, 2005.
  100. 100
    Hernandez, M.; Urcola, J. H.; Vecino, E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp. Eye Res. 2008, 86, 798806,  DOI: 10.1016/j.exer.2008.02.008
  101. 101
    Clinical Study to Investigate Safety and Efficacy of GSK933776 in Adult Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Heath: Bethesda, MD, 2017; https://clinicaltrials.gov/ct2/show/NCT01342926.
  102. 102
    AKST4290: Targeting Eotaxin—Alkahest; Alkahest, 2020; https://www.alkahest.com/pipeline/akst4290/ (accessed 2020-01-10).
  103. 103
    (a) Quigley, H. A.; Broman, A. T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006, 90, 262267,  DOI: 10.1136/bjo.2005.081224 .
    (b) Heijl, A.; Leske, M. C.; Bengtsson, B.; Hyman, L.; Hussein, M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 2002, 120, 12681279,  DOI: 10.1001/archopht.120.10.1268 .
    (c) What Is Glaucoma?; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/what-is-glaucoma/ (accessed 2019-03-15).
  104. 104
    Kwon, Y. H.; Fingert, J. H.; Kuehn, M. H.; Alward, W. L. Primary open-angle glaucoma. N. Engl. J. Med. 2009, 360, 11131124,  DOI: 10.1056/NEJMra0804630
  105. 105
    (a) Quigley, H. A. Glaucoma. Lancet 2011, 377, 13671377,  DOI: 10.1016/S0140-6736(10)61423-7 .
    (b) Greco, A.; Rizzo, M. I.; De Virgilio, A.; Gallo, A.; Fusconi, M.; de Vincentiis, M. Emerging concepts in glaucoma and review of the literature. Am. J. Med. 2016, 129, 1000.e7,  DOI: 10.1016/j.amjmed.2016.03.038
  106. 106
    Diagnosis and Treatment of Normal-Tension Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eyenet/article/diagnosis-treatment-of-normal-tension-glaucoma/ (accessed 2019-01-21).
  107. 107
    Secondary Glaucoma; Glaucoma Research Foundation, San Francisco, 2017; https://www.glaucoma.org/glaucoma/secondary-glaucoma.php/ (accessed 2019-03-12).
  108. 108
    Almasieh, M.; Wilson, A. M.; Morquette, B.; Cueva Vargas, J. L.; Di Polo, A. The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retinal Eye Res. 2012, 31, 152181,  DOI: 10.1016/j.preteyeres.2011.11.002
  109. 109
    Donegan, R. K.; Lieberman, R. L. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions: miniperspective. J. Med. Chem. 2016, 59, 788809,  DOI: 10.1021/acs.jmedchem.5b00828
  110. 110
    (a) Collaborative normal-tension glaucoma study group The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 1998, 126, 498505,  DOI: 10.1016/S0002-9394(98)00272-4 .
    (b) Jonas, J. B.; Aung, T.; Bourne, R. R.; Bron, A. M.; Ritch, R.; Panda-Jonas, S. Glaucoma. Lancet 2017, 390 (11), 21832193,  DOI: 10.1016/S0140-6736(17)31469-1
  111. 111
    (a) Glaucoma: Symptoms, Treatment and Prevention; All About Vision, 2019; https://www.allaboutvision.com/conditions/glaucoma.htm/ (accessed 2019-01-12).
    (b) Eyedrop Medicine for Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/glaucoma-eyedrop-medicine/ (accessed 2019-01-19).
    (c) Babić, N. Fixed combinations of glaucoma medications. Srp. Arh. Celok. Lek. 2015, 143, 626631,  DOI: 10.2298/SARH1510626B
  112. 112
    (a) Melamed, S.; Ben Simon, G. J.; Levkovitch-Verbin, H. Selective trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch. Ophthalmol. 2003, 121, 957960,  DOI: 10.1001/archopht.121.7.957 .
    (b) Damji, K. F.; Shah, K. C.; Rock, W. J.; Bains, H. S.; Hodge, W. G. Selective laser trabeculoplasty vargon laser trabeculoplasty: a prospective randomised clinical trial. Br. J. Ophthalmol. 1999, 83, 718722,  DOI: 10.1136/bjo.83.6.718 .
    (c) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 5567,  DOI: 10.1097/00061198-200102000-00011 .
    (d) Ayala, M.; Chen, E. Comparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucoma. Clin. Ophthalmol. 2011, 5, 14691673,  DOI: 10.2147/OPTH.S25636
  113. 113
    (a) Glaucoma Laser Trial Research Group The glaucoma laser trial (GLT) and glaucoma laser trial followup study: 7. Results. Am. J. Ophthalmol. 1995, 120, 718731,  DOI: 10.1016/S0002-9394(14)72725-4 .
    (b) Wong, M. O.; Lee, J. W.; Choy, B. N.; Chan, J. C.; Lai, J. S. Systematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucoma. Surv. Ophthalmol. 2015, 60, 3650,  DOI: 10.1016/j.survophthal.2014.06.006 .
    (c) McAlinden, C. Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic review. Eye 2014, 28, 249258,  DOI: 10.1038/eye.2013.267
  114. 114
    Gedde, S. J.; Schiffman, J. C.; Feuer, W. J.; Herndon, L. W.; Brandt, J. D.; Budenz, D. L. Treatment outcomes in the tube versus trabeculectomy (TVT) study after five years of follow-up. Am. J. Ophthalmol. 2012, 153, 789803,  DOI: 10.1016/j.ajo.2011.10.026
  115. 115
    (a) Edmunds, B.; Thompson, J.; Salmon, J.; Wormald, R. The national survey of trabeculectomy. III. early and late complications. Eye 2002, 16, 297303,  DOI: 10.1038/sj.eye.6700148 .
    (b) Spiegel, D.; Kobuch, K. Trabecular meshwork bypass tube shunt: initial case series. Br. J. Ophthalmol. 2002, 86, 12281231,  DOI: 10.1136/bjo.86.11.1228 .
    (c) Francis, B. A.; Singh, K.; Lin, S. C.; Hodapp, E.; Jampel, H. D.; Samples, J. R.; Smith, S. D. Novel glaucoma procedures: a report by the American academy of ophthalmology. Ophthalmology 2011, 118, 14661480,  DOI: 10.1016/j.ophtha.2011.03.028 .
    (d) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 5567,  DOI: 10.1097/00061198-200102000-00011
  116. 116
    (a) Prum, B. E., jr.; Herndon, L. W., jr.; Moroi, S. E.; Mansberger, S. L.; Stein, J. D.; Lim, M. C.; Rosenberg, L. F.; Gedde, S. J.; Williams, R. D. Primary angle closure preferred practice pattern guidelines. Ophthalmology 2016, 123, 140,  DOI: 10.1016/j.ophtha.2015.10.049 .
    (b) Lam, D. S. C.; Tham, C. C. Y.; Congdon, N. G.; Baig, N. Peripheral iridotomy for angle-closure glaucoma. Glaucoma 2015, 2, 708715,  DOI: 10.1016/B978-0-7020-5193-7.00072-8
  117. 117
    Glaucoma; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/glaucoma/diagnosis-treatment/drc-20372846/ (accessed 2019-02-21).
  118. 118
    Kwon, Y. H.; Kim, C. S.; Zimmerman, M. B.; Alward, W. L.; Hayreh, S. S. Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma. Am. J. Ophthalmol. 2001, 132, 4756,  DOI: 10.1016/S0002-9394(01)00912-6
  119. 119
    Chen, P. P. Blindness in patients with treated open-angle glaucoma. Ophthalmology 2003, 110, 726733,  DOI: 10.1016/S0161-6420(02)01974-7
  120. 120
    Lichter, P. R. Glaucoma clinical trials and what they mean for our patients. Am. J. Ophthalmol. 2003, 136, 136145,  DOI: 10.1016/S0002-9394(03)00143-0
  121. 121
    Weinreb, R. N.; Araie, M.; Susanna, R., Jr.; Goldberg, I.; Migdal, C.; Liebmann, J. M. Medical Treatment of Glaucoma; WGA Consensus Series; Kugler Publications: Amsterdam, 2010.
  122. 122
    Henson, D. B.; Shambhu, S. Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal study. Arch. Ophthalmol. 2006, 124, 14051408,  DOI: 10.1001/archopht.124.10.1405
  123. 123
    Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. ROCK-I and ROCK-II, two isoforms of rho-associated coil-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996, 392, 189193,  DOI: 10.1016/0014-5793(96)00811-3
  124. 124
    (a) Wang, J.; Liu, X.; Zhong, Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int. J. Oncol. 2013, 43, 13571367,  DOI: 10.3892/ijo.2013.2100 .
    (b) Wang, S. K.; Chang, R. T. An emerging treatment option for glaucoma: rho kinase inhibitors. Clin. Ophthalmol. 2014, 8, 883890,  DOI: 10.2147/OPTH.S41000 .
    (c) Chircop, M. Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells. Small GTPases 2014, 5, e29770,  DOI: 10.4161/sgtp.29770 .
    (d) Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446456,  DOI: 10.1038/nrm1128 .
    (e) Honjo, M.; Tanihara, H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn. J. Ophthalmol. 2018, 62, 109126,  DOI: 10.1007/s10384-018-0566-9 .
    (f) Ali, M. Recent advances in pharmacological therapy of glaucoma. Al-Shifa J. Ophthalmol. 2017, 13, 163165
  125. 125
    (a) Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressurelowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309315,  DOI: 10.1001/archophthalmol.2007.76 .
    (b) Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393395,  DOI: 10.1111/aos.12641
  126. 126
    Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: rsesults of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 3139,  DOI: 10.1016/j.jns.2005.06.003
  127. 127
    Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 22112215,  DOI: 10.1007/s40265-014-0333-2
  128. 128
    Ray, P.; Wright, J.; Adam, J.; Bennett, J.; Boucharens, S.; Black, D.; Cook, A.; Brown, R.; Epemolu, O.; Fletcher, D.; Haunso, A.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; Mestres, J.; de Man, J.; Morphy, R.; Rankovic, Z.; Sherborne, B.; Sherry, L.; van Straten, N.; Westwood, P.; Zaman, G. Z. R. Fragment-based discovery of 6- substituted isoquinolin-1-amine based ROCK-I inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 97101,  DOI: 10.1016/j.bmcl.2010.11.060
  129. 129
    Pan, P.; Shen, M.; Yu, H.; Li, Y.; Li, D.; Hou, T. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discovery Today 2013, 18, 13231333,  DOI: 10.1016/j.drudis.2013.09.010
  130. 130
    Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 11371140,  DOI: 10.1016/j.bmcl.2009.12.012
  131. 131
    Chen, H.-H.; Namil, A.; Severns, B.; Ward, J.; Kelly, C.; Drace, C.; McLaughlin, M. A.; Yacoub, S.; Li, B.; Patil, R.; Sharif, N.; Hellberg, M. R.; Rusinko, A.; Pang, I.-H.; Combrink, K. D. In vivo optimization of 2,3-diaminopyrazine Rho kinase inhibitors for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 2014, 24, 18751879,  DOI: 10.1016/j.bmcl.2014.03.017
  132. 132
    Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M. D.; Lin, L.; Ruiz, C.; Schurer, S. C.; Inoue, T.; Rao, P. V.; Schroter, T.; LoGrasso, P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 2008, 51, 66426645,  DOI: 10.1021/jm800986w
  133. 133
    Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2- (Aminomethyl)-5-[(pyridin-4-yl) carbamoyl] phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 64426446,  DOI: 10.1016/j.bmcl.2013.09.040
  134. 134
    deLong, M. A.; Yingling, J.; Lin, C. W.; Sherman, B.; Sturdivant, J.; Heintzelman, G.; Lathem, C.; van Haarlem, T.; Kopczynski, C. Discovery and SAR of a class of ocularly-active compounds displaying a dual mechanism of activity for the treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 3867
  135. 135
    Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 17411756,  DOI: 10.1016/j.ophtha.2018.04.040
  136. 136
    Schehlein, E. M.; Robin, A. L. Rho-associated kinase inhibitors: evolving strategies in glaucoma treatment. Drugs 2019, 79, 10311036,  DOI: 10.1007/s40265-019-01130-z
  137. 137
    Kopczynski, C.; Lin, C. W.; deLong, M.; Yingling, J.; Heintzelman, G.; Sturdivant, J.; Sherman, B.; Laethem, C.; van Haarlem, T. IOP-lowering efficacy and tolerability of AR-13324, a dual mechanism kinase inhibitor for treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 5080
  138. 138
    Wang, R. F.; Williamson, J. E.; Kopczynski, C.; Serle, J. B. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J. Glaucoma 2015, 24, 5154,  DOI: 10.1097/IJG.0b013e3182952213
  139. 139
    Li, G.; Mukherjee, D.; Navarro, I.; Ashpole, N. E.; Sherwood, J. M.; Chang, J.; Overby, D. R.; Yuan, F.; Gonzalez, P.; Kopczynski, C. C.; Farsiu, S.; Stamer, W. D. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur. J. Pharmacol. 2016, 787, 2031,  DOI: 10.1016/j.ejphar.2016.04.002
  140. 140
    Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 4051,  DOI: 10.1089/jop.2017.0023
  141. 141
    Ren, R.; Li, G.; Le, T. D.; Kopczynski, C.; Stamer, W. D.; Gong, H. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest. Ophthalmol. Visual Sci. 2016, 57, 61976209,  DOI: 10.1167/iovs.16-20189
  142. 142
    Bacharach, J.; Dubiner, H. B.; Levy, B.; Kopczynski, C. C.; Novack, G. D. Double-masked, randomized, dose response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology 2015, 122, 302307,  DOI: 10.1016/j.ophtha.2014.08.022
  143. 143
    (a) Serle, J. B.; Katz, L. J.; McLaurin, E.; Heah, T.; Ramirez-Davis, N.; Usner, D. W.; Novack, G. D.; Kopczynski, C. C. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am. J. Ophthalmol. 2018, 186, 116127,  DOI: 10.1016/j.ajo.2017.11.019 .
    (b) Levy, B.; Ramirez, N.; Novack, G. D.; Kopczynski, C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am. J. Ophthalmol. 2015, 159, 980985,  DOI: 10.1016/j.ajo.2015.01.026
  144. 144
    (a) Aerie Pharmaceuticals Reports Positive RoclatanTM (Netarsudil/Latanoprost Ophthalmic Solution) 0.02%/0.005% Phase 3 Topline Efficacy Results; Business Wire, 2019; https://www.businesswire.com/news/home/20170524006043/en/Aerie-Pharmaceuticals-Reports-Positive-Roclatan%E2%84%A2-netarsudillatanoprost-ophthalmic/ (accessed Aug 18, 2019).
    (b) Bacharach, J.; Khouri, A. S.; Kopczynski, C. C.; Heah, T.; Lewis, R. A double-masked, randomized, multi-center, active controlled, parallel group, 6-month study assessing the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution, 0.02% QD compared to timolol maleate ophthalmic solution, 0.5% bid. Am. Acad. Optom. Abst. 2017, E351
  145. 145
    Lewis, R.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339344,  DOI: 10.1136/bjophthalmol-2015-306778
  146. 146
    RoclatanTM Mercury 2 Phase 3 Topline Results; Aerie Pharmaceuticals Inc, 2016; http://investors.aeriepharma.com/static-files/fb9a0c3f-7255-4b50-97b2-450a2ba5d139/ (accessed Sep 14, 2019).
  147. 147
    (a) Tokushige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uehata, M.; Tanihara, H. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophthalmol. Visual Sci. 2007, 48, 32163222,  DOI: 10.1167/iovs.05-1617 .
    (b) Whitlock, N. A.; Harrison, B.; Mixon, T.; Yu, X.-Q.; Wilson, A.; Gerhardt, B.; Eberhart, D. E.; Abuin, A.; Rice, D. S. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J. Ocul. Pharmacol. Ther. 2009, 25, 187194,  DOI: 10.1089/jop.2008.0142
  148. 148
    Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure–lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309315,  DOI: 10.1001/archophthalmol.2007.76
  149. 149
    Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393e395,  DOI: 10.1111/aos.12641
  150. 150
    Kopczynski, C.; Novack, G. D.; Swearingen, D.; van Haarlem, T. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br. J. Ophthalmol. 2013, 97, 567572,  DOI: 10.1136/bjophthalmol-2012-302466
  151. 151
    Williams, R. D.; Novack, G. D.; van Haarlem, T.; Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 2011, 152, 834841,  DOI: 10.1016/j.ajo.2011.04.012
  152. 152
    Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 17411756,  DOI: 10.1016/j.ophtha.2018.04.040
  153. 153
    Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 22112215,  DOI: 10.1007/s40265-014-0333-2
  154. 154
    (a) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013, 131, 12881295,  DOI: 10.1001/jamaophthalmol.2013.323 .
    (b) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115) over 24 h in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol. 2015, 93, e254e260,  DOI: 10.1111/aos.12599
  155. 155
    Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am. J. Ophthalmol. 2013, 156, 731736,  DOI: 10.1016/j.ajo.2013.05.016
  156. 156
    Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Additive intraocular pressure–lowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 2015, 133, 755761,  DOI: 10.1001/jamaophthalmol.2015.0525
  157. 157
    Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Fukushima, A.; Suganami, H.; Araie, M. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016, 94, e26e34,  DOI: 10.1111/aos.12829
  158. 158
    Terao, E.; Nakakura, S.; Fujisawa, Y.; Fujio, Y.; Matsuya, K.; Kobayashi, Y.; Tabuchi, H.; Yoneda, T.; Fukushima, A.; Kiuchi, Y. Time course of conjunctival hyperemia induced by a Rho-kinase inhibitor anti-glaucoma eye drop: ripasudil 0.4%. Curr. Eye Res. 2017, 42, 738742,  DOI: 10.1080/02713683.2016.1250276
  159. 159
    Inoue, K.; Okayama, R.; Shiokawa, M.; Ishida, K.; Tomita, G. Efficacy and safety of adding ripasudil to existing treatment regimens for reducing intraocular pressure. Int. Ophthalmol. 2017, 38, 9398,  DOI: 10.1007/s10792-016-0427-9
  160. 160
    (a) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. Efficacy of the additional use of ripasudil, a Rho-kinase inhibitor, in patients with glaucoma inadequately controlled under maximum medical therapy. J. Glaucoma 2017, 26, 96100,  DOI: 10.1097/IJG.0000000000000552 .
    (b) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. Graefe's Arch. Clin. Exp. Ophthalmol. 2017, 255, 20092015,  DOI: 10.1007/s00417-017-3727-5
  161. 161
    Sato, S.; Hirooka, K.; Nitta, E.; Ukegawa, K.; Tsujikawa, A. Additive intraocular pressure lowering effects of the Rho kinase inhibitor, ripasudil in glaucoma patients not able to obtain adequate control after other maximal tolerated medical therapy. Adv. Ther. 2016, 33, 16281634,  DOI: 10.1007/s12325-016-0389-3
  162. 162
    Yamada, H.; Yoneda, M.; Inaguma, S.; Gosho, M.; Murasawa, Y.; Isogai, Z.; Zako, M. A Rho-associated kinase inhibitor protects permeability in a cell culture model of ocular disease, and reduces aqueous flare in anterior uveitis. J. Ocul. Pharmacol. Ther. 2017, 33, 176185,  DOI: 10.1089/jop.2016.0085
  163. 163
    Yasuda, M.; Takayama, K.; Kanda, T.; Taguchi, M.; Someya, H.; Takeuchi, M. Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension. PLoS One 2017, 12, e0185305,  DOI: 10.1371/journal.pone.0185305
  164. 164
    Yamamoto, K.; Maruyama, K.; Himori, N.; Omodaka, K.; Yokoyama, Y.; Shiga, Y.; Morin, R.; Nakazawa, T. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 71267136,  DOI: 10.1167/iovs.13-13842
  165. 165
    (a) Zhong, Y.; Yang, Z.; Huang, W. C.; Luo, X. Adenosine, adenosine receptors and glaucoma: An updated overview. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 28822890,  DOI: 10.1016/j.bbagen.2013.01.005 .
    (b) Shim, M. S.; Kim, K. Y.; Ju, W. K. Role of cyclic AMP in the eye with glaucoma. BMB Rep 2017, 50, 6070,  DOI: 10.5483/BMBRep.2017.50.2.200
  166. 166
    (a) Chen, J.; Runyan, S. A.; Robinson, M. R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol. 2011, 5, 667677,  DOI: 10.2147/OPTH.S15971 .
    INO-8875; Inotek Pharmaceuticals, 2019; http://www.inotekcorp.com/content/ino-8875.asp (accessed 2019-01-19).
  167. 167
    (a) Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527552.
    (b) Jacobson, K. A.; Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discovery 2006, 5, 247264,  DOI: 10.1038/nrd1983
  168. 168
    Webb, R. L.; Sills, M. A.; Chovan, J. P.; Peppard, J. V.; Francis, J. E. Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists, upon chronic administration. J. Pharmacol. Exp. Ther. 1993, 267, 287295
  169. 169
    Phase 1/2 Clinical Trial for OPA-6566, 2019; https://adisinsight.springer.com/drugs/800032852 (accessed 2019-01-21).
  170. 170
    Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125132,  DOI: 10.1089/jop.2009.0120
  171. 171
    (a) Kerwin, J. F.; Heller, M. The arginine-nitric oxide pathway a target for new drugs. Med. Res. Rev. 1994, 14, 2374,  DOI: 10.1002/med.2610140103 .
    (b) Wink, D. A.; Mitchell, J. R. Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanism of nitric oxide. Free Radical Biol. Med. 1998, 25, 434456,  DOI: 10.1016/S0891-5849(98)00092-6
  172. 172
    (a) Cavet, M. E.; Vittitow, J. L.; Impagnatiello, F.; Ongini, E.; Bastia, E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 50055015,  DOI: 10.1167/iovs.14-14515 .
    (b) Chiou, G. C. Effects of nitric oxide on eye diseases and their treatment. J. Ocul. Pharmacol. Ther. 2001, 17, 189198,  DOI: 10.1089/10807680151125555 .
    (c) Haefliger, I. O.; Meyer, P.; Flammer, J.; Lüscher, T. F. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology. Surv. Ophthalmol. 1994, 39, 123132,  DOI: 10.1016/0039-6257(94)90157-0
  173. 173
    Aliancy, J.; Stamer, W. D.; Wirostko, B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol. Ther. 2017, 6, 221232,  DOI: 10.1007/s40123-017-0094-6
  174. 174
    (a) Costa, V. P.; Harris, A.; Anderson, D.; Stodtmeister, R.; Cremasco, F.; Kergoat, H.; Lovasik, J.; Stalmans, I.; Zeitz, O.; Lanzl, I.; Gugleta, K.; Schmetterer, L. Ocular perfusion pressure in glaucoma. Acta Ophthalmol. 2014, 92, e252e266,  DOI: 10.1111/aos.12298 .
    (b) Resch, H.; Garhofer, G.; Fuchsjäger-Mayrl, G.; Hommer, A.; Schmetterer, L. Endothelial dysfunction in glaucoma. Acta Ophthalmol. 2009, 87, 412,  DOI: 10.1111/j.1755-3768.2007.01167.x
  175. 175
    Nitric Oxide (NO)-Donors: The Nicox Expertise; Nicox, 2019; http://www.nicox.com/rd/ (accessed 2019-08-21).
  176. 176
    Product and Product Candidates; Nicox, 2020 https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
  177. 177
    (a) Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V. L.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250255,  DOI: 10.1016/j.exer.2011.03.001 .
    Vyzulta for Patients with Glaucoma; Bausch & Lomb Incorporated, 2018; https://www.vyzulta.com/ (accessed 2019-08).
  178. 178
    Cavet, M. E.; Vollmer, T. R.; Harrington, K. L.; VanDerMeid, K.; Richardson, M. E. Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Invest. Ophthalmol. Visual Sci. 2015, 56, 41084116,  DOI: 10.1167/iovs.14-16015
  179. 179
    Garcia, G. A.; Ngai, P.; Mosaed, S.; Lin, K. Y. Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin. Ophthalmol. 2016, 10, 20352050,  DOI: 10.2147/OPTH.S103985
  180. 180
    Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 65586564,  DOI: 10.1167/iovs.15-17190
  181. 181
    Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2a agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250255,  DOI: 10.1016/j.exer.2011.03.001
  182. 182
    Araie, M.; Sforzolini, B. S.; Vittitow, J.; Weinreb, R. N. Evaluation of the effect of latanoprostene bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese Subjects. Adv. Ther. 2015, 32, 11281139,  DOI: 10.1007/s12325-015-0260-y
  183. 183
    Weinreb, R. N.; Ong, T.; Scassellati Sforzolini, B.; Vittitow, J. L.; Singh, K.; Kaufman, P. L. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the voyager study. Br. J. Ophthalmol. 2015, 99, 738745,  DOI: 10.1136/bjophthalmol-2014-305908
  184. 184
    Liu, J. H. K.; Slight, J. R.; Vittitow, J. L.; Scassellati Sforzolini, B.; Weinreb, R. N. Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 h. Am. J. Ophthalmol. 2016, 169, 249257,  DOI: 10.1016/j.ajo.2016.04.019
  185. 185
    Weinreb, R. N.; Scassellati Sforzolini, B.; Vittitow, J.; Liebmann, J. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the apollo study. Ophthalmology 2016, 123, 965973,  DOI: 10.1016/j.ophtha.2016.01.019
  186. 186
    Medeiros, F. A.; Martin, K. R.; Peace, J.; Scassellati Sforzolini, B.; Vittitow, J. L.; Weinreb, R. N. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular Hypertension: the LUNAR Study. Am. J. Ophthalmol. 2016, 168, 250259,  DOI: 10.1016/j.ajo.2016.05.012
  187. 187
    Kawase, K.; Vittitow, J. L.; Weinreb, R. N.; Araie, M. Long-term safety and efficacy of latanoprostene bunod 0.024% in japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER Study. Adv. Ther. 2016, 33, 16121627,  DOI: 10.1007/s12325-016-0385-7
  188. 188
    Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125132,  DOI: 10.1089/jop.2009.0120
  189. 189
    Impagnatiello, F.; Borghi, V.; Gale, D.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S.; Chong, W.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs. Exp. Eye Res. 2011, 93, 243249,  DOI: 10.1016/j.exer.2011.02.006
  190. 190
    Pipeline of Ophthalmic Therapeutics; Nicox, 2020; https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
  191. 191
    Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 65586564,  DOI: 10.1167/iovs.15-17190
  192. 192
    (a) News; Nicox, 2020; https://www.nicox.com/news-media/news/#2019/ (accessed 2020-01-10).
    (b) Nicox Presents First Data on Promising New Class of Nitric Oxide (NO)-Donating Compounds for Glaucoma at the ARVO 2019 Annual Meeting; Nicox, 2019; https://www.nicox.com/news-media/presents-first-data-on-promising-new-class-of-nitric-oxide-no-donating-compounds-for-glaucoma-at-the-arvo-2019-annual-meeting/ (accessed 2020-01-10).
  193. 193
    (a) Nicox Announces the Presentation of NCX 667 Scientific Data at AOPT 2017; Nicox, 2017; https://www.marketscreener.com/NICOX-25281955/news/Nicox-announces-the-presentation-of-NCX-667-scientific-data-at-AOPT-2017-23911286/ (accessed 2020-01-10).
    (b) NCX 667, A Novel Nitric Oxide (NO) Donor, Effectively Reduces Intraocular Pressure (IOP) in Three Models of Ocular Hypertension and Glaucoma, 2020; https://congresso.sifweb.org/archivio/cong37/abs/650.pdf/ (accessed 2020-01-10).
  194. 194
    NCX 1741, A Novel NO-donating Derivative of the Phosphodiesterase-5 Inhibitor Avanafil, Reduces IOP in Models of Ocular Hypertension and Glaucoma; Nicox, 2020; https://iovs.arvojournals.org/article.aspx?articleid=2743508 (accessed 2020-01-10).
  195. 195
    Arber, S.; Barbayannis, F. A.; Hanser, H.; Schneider, C.; Stanyon, C. A.; Bernard, O.; Caroni, P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 1998, 393, 805809,  DOI: 10.1038/31729
  196. 196
    Harrison, B. A.; Whitlock, N. A.; Voronkov, M. V.; Almstead, Z. Y.; Gu, K. J.; Mabon, R.; Gardyan, M.; Hamman, B. D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.; Zhang, Y.; Liu, Y.; Courtney, L. F.; Key, B.; Zhou, J.; Patel, N.; Yates, P. W.; Liu, Q.; Wilson, A. G.; Kimball, S. D.; Crosson, C. E.; Rice, D. S.; Rawlins, D. B. Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J. Med. Chem. 2009, 52, 65156518,  DOI: 10.1021/jm901226j
  197. 197
    Harrison, B. A.; Almstead, Z. Y.; Burgoon, H.; Gardyan, M.; Goodwin, N. C.; Healy, J.; Liu, Y.; Mabon, R.; Marinelli, B.; Samala, L.; Zhang, Y.; Stouch, T. R.; Whitlock, N. A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A. G.; Hamman, B. D.; Rice, D. S.; Rawlins, D. B. Discovery and development of LX7101, a dual LIM-Kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med. Chem. Lett. 2015, 6, 8488,  DOI: 10.1021/ml500367g
  198. 198
    (a) Ganesh, T. Prostanoid receptor EP2 as a therapeutic target. J. Med. Chem. 2014, 57, 44544465,  DOI: 10.1021/jm401431x .
    (b) Sugimoto, Y.; Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 2007, 282, 1161311617,  DOI: 10.1074/jbc.R600038200 .
    (c) Krauss, A. H.; Chen, J.; Kharlamb, A.; Burk, R. M.; Holoboski, M.; Posner, M.; Gil, D. W.; Burke, J. A.; Woodward, D. F. A selective prostanoid EP2 receptor agonist (Butaprost) normalizes glaucomatous monkey intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2002, 43, 41074108
  199. 199
    Iwamura, R.; Tanaka, M.; Okanari, E.; Kirihara, T.; Odani-Kawabata, N.; Shams, N.; Yoneda, K. Identification of a selective, non-prostanoid EP2 receptor agonist for the treatment of glaucoma: omidenepag and its prodrug omidenepag isopropyl. J. Med. Chem. 2018, 61, 68696891,  DOI: 10.1021/acs.jmedchem.8b00808
  200. 200
    Diabetic Retinopathy; Diabetes.co.uk, 2019; https://www.diabetes.co.uk/diabetes-complications/diabetic-retinopathy.html/ (accessed 2019-01-31).
    (b) Standards of Medical Care in Diabetes–2015, Summary of Revisions. Diabetes Care 2015, 38, S4. DOI: 10.2337/dc15-S003
  201. 201
    Duh, E. J.; Sun, J. K.; Stitt, A. W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017, 2, e93751,  DOI: 10.1172/jci.insight.93751
  202. 202
    Stitt, A. W.; Curtis, T. M.; Chen, M.; Medina, R. J.; McKay, G. J.; Jenkins, A.; Gardiner, T. A.; Lyons, T. J.; Hammes, H. P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retinal Eye Res. 2016, 51, 156186,  DOI: 10.1016/j.preteyeres.2015.08.001
  203. 203
    (a) Frey, T.; Antonetti, D. A. Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid. Redox Signaling 2011, 15, 12711284,  DOI: 10.1089/ars.2011.3906 .
    (b) Zhang, X.; Zeng, H.; Bao, S.; Wang, N.; Gillies, M. C. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014, 4, 27,  DOI: 10.1186/2045-3701-4-27
  204. 204
    (a) Romero-Aroca, P.; Baget-Bernaldiz, M.; Pareja-Rios, A.; Lopez-Galvez, M.; Navarro-Gil, R.; Verges, R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J. Diabetes Res. 2016, 2016, 2156273,  DOI: 10.1155/2016/2156273 .
    Diabetic Retinopathy; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/diabetic-retinopathy/symptoms-causes/syc-20371611// (accessed 2019-02-21).
  205. 205
    (a) Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54, 16151625,  DOI: 10.2337/diabetes.54.6.1615 .
    (b) Tarr, J. M.; Kaul, K.; Chopra, M.; Kohner, E. M.; Chibber, R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. 2013, 2013, 343560,  DOI: 10.1155/2013/343560
  206. 206
    Yuuki, T.; Kanda, T.; Kimura, Y.; Kotajima, N.; Tamura, J.; Kobayashi, I.; Kishi, S. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J. Diab. Complic. 2001, 15, 257259,  DOI: 10.1016/S1056-8727(01)00155-6
  207. 207
    (a) Tien, T.; Zhang, J.; Muto, T.; Kim, D.; Sarthy, V. P.; Roy, S. High glucose induces mitochondrial dysfunction in retinal muller cells: Implications for diabetic retinopathy. Invest. Ophthalmol. Visual Sci. 2017, 58, 29152921,  DOI: 10.1167/iovs.16-21355 .
    (b) Sasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. Diabetologia 2010, 53, 971979,  DOI: 10.1007/s00125-009-1655-6
  208. 208
    (a) Mitchell, P.; Bandello, F.; Schmidt-Erfurth, U.; Lang, G. E.; Massin, P.; Schlingemann, R. O.; Sutter, F.; Simader, C.; Burian, G.; Gerstner, O.; Weichselberger, A. the restore study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011, 118, 615625,  DOI: 10.1016/j.ophtha.2011.01.031 .
    (b) Sultan, M. B.; Zhou, D.; Loftus, J.; Dombi, T.; Ice, K. S. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011, 118, 11071118,  DOI: 10.1016/j.ophtha.2011.02.045 .
    (c) Heier, J. S.; Korobelnik, J. F.; Brown, D. M.; Schmidt-Erfurth, U.; Do, D. V.; Midena, E.; Boyer, D. S.; Terasaki, H.; Kaiser, P. K.; Marcus, D. M.; Nguyen, Q. D.; Jaffe, G. J.; Slakter, J. S.; Simader, C.; Soo, Y.; Schmelter, T.; Vitti, R.; Berliner, A. J.; Zeitz, O.; Metzig, C.; Holz, F. G. Intravitreal aflibercept for diabetic macular edema: 148-week results from the vista and vivid studies. Ophthalmology 2016, 123, 23762385,  DOI: 10.1016/j.ophtha.2016.07.032 .
    (d) The Diabetic Retinopathy Clinical Research Network Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 2015, 372, 11931203,  DOI: 10.1056/NEJMoa1414264
  209. 209
    (a) Elman, M. J.; Aiello, L. P.; Beck, R. W.; Bressler, N. M.; Bressler, S. B.; Edwards, A. R.; Ferris, F. L.; Friedman, S. M.; Glassman, A. R.; Miller, K. M.; Scott, I. U.; Stockdale, C. R.; Sun, J. K. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010, 117, 10641077,  DOI: 10.1016/j.ophtha.2010.02.031 .
    (b) Pacella, F.; Romano, M. R.; Turchetti, P.; Tarquini, G.; Carnovale, A.; Mollicone, A.; Mastromatteo, A.; Pacella, E. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int. J. Ophthalmol. 2016, 9, 14271432,  DOI: 10.18240/ijo.2016.10.10
  210. 210
    (a) Wroblewski, J. J.; Hu, A. Y. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study. Ophthalmic Surg. Lasers Imag. Retina 2016, 47, 914923,  DOI: 10.3928/23258160-20161004-04 .
    (b) Campochiaro, P. A.; Khanani, A.; Singer, M.; Patel, S.; Boyer, D.; Dugel, P.; Kherani, S.; Withers, B.; Gambino, L.; Peters, K.; Brigell, M. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology 2016, 123, 17221730,  DOI: 10.1016/j.ophtha.2016.04.025 .
    (c) Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema (RUBY). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02712008/ (accessed 2020-01-05).
    (d) A Study of Faricimab (RO6867461) in Participants With Center-involving Diabetic Macular Edema (BOULEVARD). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2019; https://clinicaltrials.gov/ct2/show/NCT02699450/ (accesed Jan 5, 2020).
  211. 211
    (a) Safety Study of Intravitreal EBI-031 Given as a Single or Repeat Injection to Subjects with Diabetic Macular Edema; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2016; https://clinicaltrials.gov/ct2/show/NCT02842541/ (accesssed Jan 20, 2019).
    (b) Ranibizumab for Edema of the Macula in Diabetes: Protocol 4 with Tocilizumab: the read-4 Study; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02511067/ (accessed 2019-01-20).
  212. 212
    (a) Early Treatment Diabetic Retinopathy Study Research Group Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. early treatment diabetic retinopathy study report number 2. Ophthalmology 1987, 94, 761774,  DOI: 10.1016/S0161-6420(87)33527-4 .
    (b) Patz, A.; Fine, S.; Finkelstein, D.; Prout, T.; Aiello, L.; Bradley, R.; Briones, J. C.; Myers, F.; Bresnick, G.; de Venecia, G.; Stevens, T. S.; Wallow, I. H.L.; Chandra, S. R.; Norton, E.; Blankenship, G.; Harris, J.; Knobloch, W.; Goetz, F.; Ramsay, R. C.; McMeel, J. W.; Martin, D.; Goldberg, M.; Huamonte, F.; Peyman, G.; Straatsma, B.; Kopelow, S.; van Heuven, W.A.J.; Kassoff, A.; Feman, S.; Watzke, R.; Mensher, J.; Tasman, W.; Annesley, W.; Leonard, B.; Canny, C.; Joffe, L.; Pheasant, T.; Riekhof, F. T.; Dahl, M.; Bohart, W.; Clarke, D.; Berrocal, J.; Ramos-Umpierre, A.; Velazquez, G.; Margherio, R.; Nachazel, D.; McLean, E.; Guzak, S.; Knatterud, G.; Klimt, C.; Hillis, A.; Makuc, D.; Davis, M.; MacCormick, A.; Magli, Y.; Segal, P. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978, 85, 82106,  DOI: 10.1016/S0161-6420(78)35693-1
  213. 213
    (a) Blumenkranz, M. S.; Yellachich, D.; Andersen, D. E.; Wiltberger, M. W.; Mordaunt, D.; Marcellino, G. R.; Palanker, D. Semiautomated patterned scanning laser for retinal photocoagulation. Retina 2006, 26, 370376,  DOI: 10.1097/00006982-200603000-00024 .
    (b) Vujosevic, S.; Martini, F.; Convento, E.; Longhin, E.; Kotsafti, E.; Parrozzani, R.; Midena, E. Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. Curr. Med. Chem. 2013, 20, 32673271,  DOI: 10.2174/09298673113209990030 .
    (c) Neubauer, A. S.; Langer, J.; Liegl, R.; Haritoglou, C.; Wolf, A.; Kozak, I.; Seidensticker, F.; Ulbig, M.; Freeman, W. R.; Kampik, A.; Kernt, M. Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin. Ophthalmol. 2013, 7, 121128,  DOI: 10.2147/OPTH.S38559
  214. 214
    (a) Paradies, G.; Petrosillo, G.; Paradies, V.; Ruggiero, F. M. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 2009, 45, 643650,  DOI: 10.1016/j.ceca.2009.03.012 .
    (b) Alam, N. M.; Mills, W. C. T.; Wong, A. A.; Douglas, R. M.; Szeto, H. H.; Prusky, G. T. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis. Models & Mech. 2015, 8, 701710,  DOI: 10.1242/dmm.020248 .
    (c) Gebka, A.; Serkies-Minuth, E.; Raczynska, D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflammation 2014, 2014, 131538,  DOI: 10.1155/2014/131538
  215. 215
    (a) Li, S. Y.; Fu, Z. J.; Ma, H.; Jang, W. C.; So, K. F.; Wong, D.; Lo, A. C. Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusion. Invest. Ophthalmol. Visual Sci. 2009, 50, 836843,  DOI: 10.1167/iovs.08-2310 .
    (b) Li, S. Y.; Fung, F. K.; Fu, Z. J.; Wong, D.; Chan, H. H.; Lo, A. C. Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: In vivo and in vitro studies. Invest. Ophthalmol. Visual Sci. 2012, 53, 59765984,  DOI: 10.1167/iovs.12-10007 .
    (c) McVicar, C. M.; Hamilton, R.; Colhoun, L. M.; Gardiner, T. A.; Brines, M.; Cerami, A.; Stitt, A. W. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes 2011, 60, 29953005,  DOI: 10.2337/db11-0026 .
    (d) Canning, P.; Kenny, B. A.; Prise, V.; Glenn, J.; Sarker, M. H.; Hudson, N.; Brandt, M.; Lopez, F. J.; Gale, D.; Luthert, P. J.; Adamson, P.; Turowski, P.; Stitt, A. W. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 72137218,  DOI: 10.1073/pnas.1514213113
  216. 216
    KalVista for DME; KalVista Pharmaceuticals, 2020; https://www.kalvista.com/products-pipeline/kalvista-dme/ (accessed 2020-03-20).
  217. 217
    Murugesan, N.; Clermont, A. C.; Rushbrooke, L. J.; Robson, P. A.; Thoonen, R.; Pethen, S. J.; Hampton, S. L.; Feener, E. P. A novel oral plasma kallikrein (PKal) inhibitor KV123833 blocks VEGF-mediated retinal vascular hyperpermeability in a murine model of retinal edema. Invest. Ophthal. Vis. Sc. 2018, 59, 3464
  218. 218
    Bhatwadekar, A. D.; Kansara, V. S.; Ciulla, T. A. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin. Invest. Drugs 2020, 29, 237244,  DOI: 10.1080/13543784.2020.1723078
  219. 219
    Novel Oral Plasma Kallikrein (PKa) Inhibitors KV998052 and KV998054 Ameliorate VEGF-Induced Retinal Thickening in a Murine Model of Retinal Edema; KalVista, 2019; https://www.kalvista.com/healthcare-providers/publications/ (accesed 2020-03-15).
  220. 220
    KalVista Pharmaceuticals Announces Collaboration with Merck; Business Wire, 2017; https://www.businesswire.com/news/home/20171010005129/en/KalVista-Pharmaceuticals-Announces-Collaboration-Merck/ (accessed 2020-03-20).
  221. 221
    KalVista Plans to Continue Work on Diabetic Macular Edema After Merck Walks Away from Deal; BioSpace, 2020; https://www.biospace.com/article/merck-walks-away-from-kalvista-option-deal/ (accessed 2020-03-20).
  222. 222
    Oxurion NV Reports Additional Positive Topline Data from Phase 1 with THR-149, a Novel, Potent Plasma Kallikrein Inhibitor for DME; Global Newswire, 2019; https://www.globenewswire.com/news-release/2019/09/09/1912924/0/en/Oxurion-NV-Reports-Additional-Positive-Topline-Data-from-Phase-1-with-THR-149-a-Novel-Potent-Plasma-Kallikrein-Inhibitor-for-DME.html/ (accessed 2020-03-20).
  223. 223
    Phipps, J. A.; Clermont, A. C.; Sinha, S.; Chilcote, T. J.; Bursell, S. E.; Feener, E. P. Plasma kallikrein mediates angiotensin II Type 1 receptor–stimulated retinal vascular permeability. Hypertension 2009, 53, 175181,  DOI: 10.1161/HYPERTENSIONAHA.108.117663
  224. 224
    Calton, M. A.; Ma, J. A.; Chang, E.; Litt, J. L.; Chang, S. S.; Estiarte, M. A.; Shiau, T. P.; Datta, A.; Kita, D. B. An orally dosed plasma kallikrein inhibitor decreases retinal vascular permeability in a rat model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018, 59, 3576
  225. 225
    (a) The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye workshop. Ocul. Surf. 2007, 5, 93107. DOI: 10.1016/S1542-0124(12)70082-4
    (b) Facts About Dry Eye; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/dryeye/dryeye/ (accessed 2019-01-29).
    (c) Hessen, A. W.; Akpek, E. K. Dry eye: an inflammatory ocular disease. J. Ophthalmic Vis. Res. 2014, 9, 240250
  226. 226
    (a) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International dry eye workshop. Ocul. Surf. 2007, 5, 7592. DOI: 10.1016/S1542-0124(12)70081-2
    (b) Clayton, J. A. Dry eye. N. Engl. J. Med. 2018, 378, 22122223,  DOI: 10.1056/NEJMra1407936 .
    (c) Hartstein, I.; Khwarg, S.; Przydryga, J. An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult population. Curr. Med. Res. Opin. 2005, 21, 255260,  DOI: 10.1185/030079905X26252 .
    (d) Bremond-Gignac, D.; Gicquel, J. J.; Chiambaretta, F. Pharmacokinetic evaluation of diquafosol tetrasodium for the treatment of Sjogren’s syndrome. Expert Opin. Drug Metab. Toxicol. 2014, 10, 905913,  DOI: 10.1517/17425255.2014.915026 .
    (e) Lim, A.; Wenk, M. R.; Tong, L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol. Med. 2015, 21, 736748,  DOI: 10.1016/j.molmed.2015.10.001 .
    (f) Narayanaswamy, A.; Leung, C. K.; Istiantoro, D. V.; Perera, S. A.; Ho, C. L.; Nongpiur, M. E.; Baskaran, M.; Htoon, H. M.; Wong, T. T.; Goh, D.; Su, D. H.; Belkin, M.; Aung, T. Efficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trial. JAMA Ophthalmol 2015, 133, 206212,  DOI: 10.1001/jamaophthalmol.2014.4893
  227. 227
    (a) Sall, K.; Stevenson, O. D.; Mundorf, T. K.; Reis, B. L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000, 107, 631639,  DOI: 10.1016/S0161-6420(99)00176-1 .
    (b) FDA Approves New Medication for Dry Eye Disease; US Food and Drug Administration, 2017; https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-dry-eye-disease/ (accessed 2019-02-21).
  228. 228
    Lee, Y. B.; Koh, J. W.; Hyon, J. Y.; Wee, W. R.; Kim, J. J.; Shin, Y. J. Sleep deprivation reduces tear secretion and impairs the tear film. Invest. Ophthalmol. Visual Sci. 2014, 55, 35253531,  DOI: 10.1167/iovs.14-13881
  229. 229
    Meibomian Gland Dysfunction (MGD); American Academy of Ophthalmology, 2019; https://eyewiki.aao.org/Meibomian_Gland_Dysfunction_(MGD) (accessed 2019-01-20).
  230. 230
    Rocha, E. M.; Wickham, L. A.; da Silveira, L. A.; Krenzer; Yu; Toda; Sullivan, D. A.; Sullivan, B. D. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br. J. Ophthalmol. 2000, 84, 7684,  DOI: 10.1136/bjo.84.1.76
  231. 231
    Haber, S. L.; Benson, V.; Buckway, C. J.; Gonzales, J. M.; Romanet, D.; Scholes, B. Lifitegrast: a novel drug for patients with dry eye disease. Ther. Adv. Ophthalmol. 2019, 11, 2515841419870366,  DOI: 10.1177/2515841419870366
  232. 232
    (a) Facts About Cataract; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/cataract/cataract_facts/ (accessed Jan 21, 2019).
    (b) Gimbel, H. V.; Dardzhikova, A. A. Consequences of waiting for cataract surgery. Curr. Opin. Ophthalmol. 2011, 22, 2830,  DOI: 10.1097/ICU.0b013e328341425d .
    (c) Priority Eye Diseases; World Health Organization, 2019; http://www9.who.int/blindness/causes/priority/en/ (accessed 2019-04-31).
  233. 233
    (a) Reddy, S. C. Electric cataract: a case report and review of the literature. Eur. J. Ophthalmol. 1999, 9, 134138,  DOI: 10.1177/112067219900900211 .
    (b) Ram, J.; Gupta, R. Petaloid Cataract. N. Engl. J. Med. 2016, 374, e22,  DOI: 10.1056/NEJMicm1507349 .
    (c) Hejtmancik, J. F.; Smaoui, N. Molecular genetics of cataract. Dev. Ophthalmol. 2003, 37, 6782,  DOI: 10.1159/000072039
  234. 234
    (a) Yu, J.; Asche, C. V.; Fairchild, C. J. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011, 30, 379387,  DOI: 10.1097/ICO.0b013e3181f7f363 .
    (b) Bollinger, K. E.; Langston, R. H. What can patients expect from cataract surgery. Cleve Clin. J. Med. 2008, 75, 193196,  DOI: 10.3949/ccjm.75.3.193 .
    (c) Alshamrani, A. Z. Cataracts pathophysiology and managements. Egypt. J. Hosp. Med. 2018, 70, 151154,  DOI: 10.12816/0042978
  235. 235
    Davis, G. The evolution of cataract surgery. Mol. Med. 2016, 113, 5862
  236. 236
    Liu, Y. C.; Wilkins, M.; Kim, T.; Malyugin, B.; Mehta, J. S. Cataracts. Lancet 2017, 390, 600612,  DOI: 10.1016/S0140-6736(17)30544-5
  237. 237
    (a) Eisenberg, J. S. Are premium IOLS set to breakout? the market forces that have held them back may be about the change. Ophthalmol. Manage. 2013, 17, 3638.
    (b) Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 10881097,  DOI: 10.1016/j.jcrs.2015.04.005
  238. 238
    (a) Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 3539,  DOI: 10.1097/ICU.0000000000000016 .
    (b) Chen, X.; Yuan, F.; Wu, L. Meta-analysis of intraocular lens power calculation after laser refractive surgery in myopic eyes. J. Cataract Refractive Surg. 2016, 42, 163170,  DOI: 10.1016/j.jcrs.2015.12.005
  239. 239
    Mcgoldrick, K. E. Cataract extraction. In Decision Making in Anesthesiology: An Algorithm Approach, 4th ed..; Mosby/Elsevier: Maryland Heights, MO, 2007; pp 518519.
  240. 240
    (a) Zaczek, A.; Olivestedt, G.; Zetterström, C. Visual outcome after phacoemulsification and IOL implantation in diabetic patients. Br. J. Ophthalmol. 1999, 83, 10361041,  DOI: 10.1136/bjo.83.9.1036 .
    (b) Alezzandrini, A.; Arevalo, J. F. Phacoemulsification and pars plana vitrectomy. Retina Today 2010, 3437
  241. 241
    Shi, C.; Yuan, J.; Zee, B. Pain perception of the first eye versus the second eye during phacoemulsification under local anesthesia for patients going through cataract surgery: a systematic review and meta-analysis. J. Ophthalmol. 2019, 2019, 4106893,  DOI: 10.1155/2019/4106893
  242. 242
    McMonnies, C. W. The potential role of neuropathic mechanisms in dry eye syndromes. J. Optom. 2017, 10, 513,  DOI: 10.1016/j.optom.2016.06.002
  243. 243
    Asbell, P. A.; Dualan, I.; Mindel, J.; Brocks, D.; Ahmad, M.; Epstein, S. Age-related cataract. Lancet 2005, 365, 599609,  DOI: 10.1016/S0140-6736(05)70803-5
  244. 244
    Rong, X.; He, W.; Zhu, Q.; Qian, D.; Lu, Y.; Zhu, X. Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulas. J. Cataract Refractive Surg. 2019, 45, 732737,  DOI: 10.1016/j.jcrs.2018.12.025
  245. 245
    Khandelwal, S. S.; Jun, J. J.; Mak, S.; Booth, M. S.; Shekelle, P. G. Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysis. Graefe's Arch. Clin. Exp. Ophthalmol. 2019, 257, 863875,  DOI: 10.1007/s00417-018-04218-6
  246. 246
    Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 10881097,  DOI: 10.1016/j.jcrs.2015.04.005
  247. 247
    Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 3539,  DOI: 10.1097/ICU.0000000000000016
  248. 248
    van Kooten, T. G.; Koopmans, S. A.; Terwee, T.; Langner, S.; Stachs, O.; Guthoff, R. F. Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit model. Acta Ophthalmol. 2019, 97, e860e870,  DOI: 10.1111/aos.14096
  249. 249
    Donaldson, K. E.; Braga-Mele, R.; Cabot, F.; Davidson, R.; Dhaliwal, D. K.; Hamilton, R.; Jackson, M.; Patterson, L.; Stonecipher, K.; Yoo, H. Femtosecond laser-assisted cataract surgery. J. Cataract Refractive Surg. 2013, 39, 17531763,  DOI: 10.1016/j.jcrs.2013.09.002
  250. 250
    Karahan, E.; Er, D.; Kaynak, S. An Overview of Nd: YAG laser capsulotomy. Med. Hypothesis Discovery Innov. Ophthalmol. 2014, 3, 4550
  251. 251
    Ntsoane, M. D.; Oduntan, O. A.; Mpolokeng, B. L. Utilisation of public eye care services by the rural community residents in the Capricorn district, Limpopo Province, South Africa. African J. Prim. Health Care Fam. Med. 2012, 4, a412,  DOI: 10.4102/phcfm.v4i1.412
  252. 252
    Rabiu, M. M. Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern Nigeria. Br. J. Ophthalmol. 2001, 85, 776780,  DOI: 10.1136/bjo.85.7.776
  253. 253
    Geneau, R.; Massae, P.; Courtright, P.; Lewallen, S. Using qualitative methods to understand the determinants of patients’ willingness to pay for cataract surgery: a study in Tanzania. Social science & medicine 2008, 66, 558568,  DOI: 10.1016/j.socscimed.2007.09.016
  254. 254
    Ntsoane, M.; Oduntan, O. A review of factors influencing the utilization of eye care services. Afr. Vis. Eye Health 2010, 69, 182192,  DOI: 10.4102/aveh.v69i4.143
  255. 255
    Fadamiro, C.; Ajite, K. Barriers to utilization of cataract surgical services in ekiti state, south western nigeria. Nig. J. Clin. Prac. 2017, 20, 783786
  256. 256
    Atiyeh, B. S.; Gunn, S. W. A.; Hayek, S. N. Provision of essential surgery in remote and rural areas of developed as well as low and middle income countries. Int. J. Sur. 2010, 8, 581585,  DOI: 10.1016/j.ijsu.2010.07.291
  257. 257
    Makley, L. N.; McMenimen, K. A.; DeVree, B. T.; Goldman, J. W.; McGlasson, B. N.; Rajagopal, P.; Dunyak, B. M.; McQuade, T. J.; Thompson, A. D.; Sunahara, R.; Klevit, R. E.; Andley, U. P.; Gestwicki, J. E. Pharmacological chaperone for α-Crystallin partially restores transparency in cataract models. Science 2015, 350, 674677,  DOI: 10.1126/science.aac9145
  258. 258
    Molnar, K. S.; Dunyak, B. M.; Su, B.; Izrayelit, Y.; McGlasson-Naumann, B.; Hamilton, P. D.; Qian, M.; Covey, D. F.; Gestwicki, J. E.; Makley, L. H.; Andley, U. P. Mechanism of action of VP1–001 in cryAB(R120G)- associated and age-related cataracts. Invest. Ophthalmol. Visual Sci. 2019, 60, 33203321,  DOI: 10.1167/iovs.18-25647
  259. 259
    New Drugs You May Have Missed. Review of Cornea and Contact Lenses 2014, https://www.reviewofcontactlenses.com/article/new-drugs-you-may-have-missed/ (accessed 2020-03-20).
  260. 260
    Campos-Sandoval, J. A.; Redondo, C.; Kinsella, G. K.; Pal, A.; Jones, G.; Eyre, G. S.; Hirst, S. C.; Findlay, J. B. Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J. Med. Chem. 2011, 54, 43784387,  DOI: 10.1021/jm200256g
  261. 261
    Cioffi, C. L.; Dobri, N.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Golden, K. C.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Racz, B.; Qin, Q.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2014, 57, 77317757,  DOI: 10.1021/jm5010013
  262. 262
    Wang, Y.; Connors, R.; Fan, P.; Wang, X.; Wang, Z.; Liu, J.; Kayser, F.; Medina, J. C.; Johnstone, S.; Xu, H.; Thibault, S.; Walker, N.; Conn, M.; Zhang, Y.; Liu, Q.; Grillo, M. P.; Motani, A.; Coward, P.; Wang, Z. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4. Bioorg. Med. Chem. Lett. 2014, 24, 28852891,  DOI: 10.1016/j.bmcl.2014.04.089
  263. 263
    Stanton, C. M.; Yates, J. R.; den Hollander, A. I.; Seddon, J. M.; Swaroop, A.; Stambolian, D.; Fauser, S.; Hoyng, C.; Yu, Y.; Atsuhiro, K.; Branham, K.; Othman, M.; Chen, W.; Kortvely, E.; Chalmers, K.; Hayward, C.; Moore, A. T.; Dhillon, B.; Ueffing, M.; Wright, A. F. Complement factor D in age-related macular degeneration. Invest. Ophthalmol. Visual Sci. 2011, 52, 88288834,  DOI: 10.1167/iovs.11-7933
  264. 264
    Vulpetti, A.; Ostermann, N.; Randl, S.; Yoon, T.; Mac Sweeney, A.; Cumin, F.; Lorthiois, E.; Rudisser, S.; Erbel, P.; Maibaum, J. Discovery and design of first benzylamine-based ligands binding to an unlocked conformation of the complement factor D. ACS Med. Chem. Lett. 2018, 9, 490495,  DOI: 10.1021/acsmedchemlett.8b00104
  265. 265
    Zhang, M.; Yang, X. Y.; Tang, W.; Groeneveld, T. W. L.; He, P. L.; Zhu, F. H.; Li, J.; Lu, W.; Blom, A. M.; Zuo, J. P.; Nan, F. J. Discovery and structural modification of 1-Phenyl-3-(1-phenylethyl)urea derivatives as inhibitors of complement. ACS Med. Chem. Lett. 2012, 3, 317321,  DOI: 10.1021/ml300005w
  266. 266
    Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 92739286,  DOI: 10.1021/acs.jmedchem.5b01227
  267. 267
    Adams, C. M.; Anderson, K.; Artman, G.; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, L. F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 16221635,  DOI: 10.1021/acs.jmedchem.7b01731
  268. 268
    Basavarajappa, H. D.; Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magaña, C.; Shadmand, M.; Vayl, A.; Rajashekhar, G.; Kim, E. Y.; Suh, Y. G.; Lee, K.; Seo, S. Y.; Corson, T. W. Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization. J. Med. Chem. 2015, 58, 50155027,  DOI: 10.1021/acs.jmedchem.5b00449
  269. 269
    Palanki, M. S. S.; Akiyama, H.; Campochiaro, P.; Cao, J.; Chow, C. P.; Dellamary, L.; Doukas, J.; Fine, R.; Gritzen, C.; Hood, J. D.; Hu, S.; Kachi, S.; Kang, X.; Klebansky, B.; Kousba, A.; Lohse, D.; Mak, C. C.; Martin, M.; McPherson, A.; Pathak, V. P.; Renick, J.; Soll, R.; Umeda, N.; Yee, S.; Yokoi, K.; Zeng, B.; Zhu, H.; Noronha, G. Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J. Med. Chem. 2008, 51, 15461559,  DOI: 10.1021/jm7011276
  270. 270
    Olivieri, M.; Amata, E.; Vinciguerra, S.; Fiorito, J.; Giurdanella, G.; Drago, F.; Caporarello, N.; Prezzavento, O.; Arena, E.; Salerno, L.; Rescifina, A.; Lupo, G.; Anfuso, C. D.; Marrazzo, A. Antiangiogenic effect of (±)-haloperidol metabolite II valproate ester [(±)-MRJF22] in human microvascular retinal endothelial cells. J. Med. Chem. 2016, 59, 99609966,  DOI: 10.1021/acs.jmedchem.6b01039
  271. 271
    Papadaki, T.; Tsilimbaris, M.; Thermos, K.; Karavellas, M.; Samonakis, D.; Papapdakis, A.; Linardakis, M.; Kouromalis, E.; Pallikaris, I. The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trial. Retina 2003, 23, 800807,  DOI: 10.1097/00006982-200312000-00010
  272. 272
    Wolkenberg, S. E.; Zhao, Z.; Thut, C.; Maxwell, W. J.; McDonald, T. P.; Kinose, F.; Reilly, M.; Lindsley, C. W.; Hartman, G. D. Design, synthesis, and evaluation of novel 3, 6-Diaryl-4- amino alkoxy quinolines as selective agonists of somatostatin receptor subtype 2. J. Med. Chem. 2011, 54, 23512358,  DOI: 10.1021/jm101501b
  273. 273
    Arjamaa, O.; Nikinmaa, M.; Salminen, A.; Kaarniranta, K. Regulatory role of HIF-1 α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res. Rev. 2009, 8, 349358,  DOI: 10.1016/j.arr.2009.06.002
  274. 274
    Oh, S. H.; Woo, J. K.; Yazici, Y. D.; Myers, J. N.; Kim, W. Y.; Jin, Q.; Hong, S. S.; Park, H. J.; Suh, Y. G.; Kim, K. W.; Hong, W. K.; Lee, H. Y. Structural basis for depletion of heat shock protein 90 client proteins by deguelin. J. Natl. Canc. Inst. 2007, 99, 949961,  DOI: 10.1093/jnci/djm007
  275. 275
    (a) Lee, S.; An, H.; Chang, D. J.; Jang, J.; Kim, K.; Sim, J.; Lee, J.; Suh, Y. G. Total synthesis of (−)-deguelin via an iterative pyran-ring formation strategy. Chem. Commun. 2015, 51, 90269029,  DOI: 10.1039/C5CC02215K .
    (b) Chang, D. J.; An, H.; Kim, K. S.; Kim, H. H.; Jung, J.; Lee, J. M.; Kim, N. J.; Han, Y. T.; Yun, H.; Lee, S.; Lee, G.; Lee, S.; Lee, J. S.; Cha, J. H.; Park, J. H.; Park, J. W.; Lee, S. C.; Kim, S. G.; Kim, J. H.; Lee, H. Y.; Kim, K. W.; Suh, Y. G. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J. Med. Chem. 2012, 55, 1086310884,  DOI: 10.1021/jm301488q
  276. 276
    An, H.; Lee, S.; Lee, J. M.; Jo, D. H.; Kim, J.; Jeong, Y. S.; Heo, M. J.; Cho, C. S.; Choi, H.; Seo, J. H.; Hwang, S.; Lim, J.; Kim, T.; Jun, H. O.; Sim, J.; Lim, C.; Hur, J.; Ahn, J.; Kim, H. S.; Seo, S. Y.; Na, Y.; Kim, S. H.; Lee, J.; Lee, J.; Chung, S. J.; Kim, Y. M.; Kim, K. W.; Kim, S. G.; Kim, J. H.; Suh, Y. G. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy. J. Med. Chem. 2018, 61, 92669286,  DOI: 10.1021/acs.jmedchem.8b00971
  277. 277
    Jin, H.; Randazzo, J.; Zhang, P.; Kador, P. F. Multifunctional antioxidants for the treatment of age-related diseases. J. Med. Chem. 2010, 53, 11171127,  DOI: 10.1021/jm901381j
  278. 278
    Joshi, D.; Field, J.; Murphy, J.; Abdelrahim, M.; Schönherr, H.; Sparrow, J. R.; Ellestad, E. G.; Nakanishi, K.; Zask, A. Synthesis of antioxidants for prevention of age-related macular degeneration. J. Nat. Prod. 2013, 76, 450454,  DOI: 10.1021/np300769c
  279. 279
    Deng, H.; Li, T.; Xie, J.; Huang, N.; Gu, Y.; Zhao, J. Synthesis and bio-evaluation of novel hypocrellin derivatives. potential photosensitizers for photodynamic therapy of age-related macular degeneration. Dyes Pigm. 2013, 99, 930939,  DOI: 10.1016/j.dyepig.2013.06.037
  280. 280
    Carta, F.; Aggarwal, M.; Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C. T. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in Vivo. J. Med. Chem. 2012, 55, 17211730,  DOI: 10.1021/jm300031j
  281. 281
    Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J. Med. Chem. 2013, 56, 46914700,  DOI: 10.1021/jm400414j
  282. 282
    Vullo, D.; Durante, M.; Di Leva, F. S.; Cosconati, S.; Masini, E.; Scozzafava, A.; Novellino, E.; Supuran, C. T.; Carta, F. Monothiocarbamates strongly inhibit carbonic anhydrases in vitro and possess intraocular pressure lowering activity in an animal model of glaucoma. J. Med. Chem. 2016, 59, 58575867,  DOI: 10.1021/acs.jmedchem.6b00462
  283. 283
    Bozdag, M.; Pinard, M.; Carta, F.; Masini, E.; Scozzafava, A.; McKenna, R.; Supuran, C. T. A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects. J. Med. Chem. 2014, 57, 96739686,  DOI: 10.1021/jm501497m
  284. 284
    Bozdag, M.; Ferraroni, M.; Carta, F.; Vullo, D.; Lucarini, L.; Orlandini, E.; Rossello, A.; Nuti, E.; Scozzafava, A.; Masini, E.; Supuran, C. T. Structural insights on carbonic anhydrase inhibitory action, isoform selectivity, and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups. J. Med. Chem. 2014, 57, 91529167,  DOI: 10.1021/jm501314c
  285. 285
    Carta, F.; Osman, S. M.; Vullo, D.; Gullotto, A.; Winum, J. Y.; AlOthman, Z.; Masini, E.; Supuran, C. T. Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action. J. Med. Chem. 2015, 58, 40394045,  DOI: 10.1021/acs.jmedchem.5b00383
  286. 286
    Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.; Supuran, C. T.; Poulsen, S. A. A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click- tailing. J. Med. Chem. 2006, 49, 65396548,  DOI: 10.1021/jm060967z
  287. 287
    Pacchiano, F.; Carta, F.; McDonald, P. C.; Lou, Y.; Vullo, D.; Scozzafava, A.; Dedhar, S.; Supuran, C. T. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 2011, 54, 18961902,  DOI: 10.1021/jm101541x
  288. 288
    Nocentini, A.; Ferraroni, M.; Carta, F.; Ceruso, M.; Gratteri, P.; Lanzi, C.; Masini, E.; Supuran, C. T. Benzenesulfonamides incorporating flexible triazole moieties are highly effective carbonic anhydrase inhibitors: synthesis and kinetic, crystallographic, computational, and intraocular pressure lowering investigations. J. Med. Chem. 2016, 59, 1069210704,  DOI: 10.1021/acs.jmedchem.6b01389
  289. 289
    Huang, Q.; Rui, E. Y.; Cobbs, M.; Dinh, D. M.; Gukasyan, H. J.; Lafontaine, J. A.; Mehta, S.; Patterson, B. D.; Rewolinski, D. A.; Richardson, P. F.; Edwards, M. P. Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure. J. Med. Chem. 2015, 58, 28212833,  DOI: 10.1021/acs.jmedchem.5b00043
  290. 290
    Yin, Y.; Lin, L.; Ruiz, C.; Khan, S.; Cameron, M. D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schröter, T.; Lograsso, P. V.; Feng, Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J. Med. Chem. 2013, 56, 35683581,  DOI: 10.1021/jm400062r
  291. 291
    Fang, X.; Yin, Y.; Chen, Y. T.; Yao, L.; Wang, B.; Cameron, M. D.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; LoGrasso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem. 2010, 53, 57275737,  DOI: 10.1021/jm100579r
  292. 292
    Wu, F.; Buttner, F.; Chen, R.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem, M.; Kerr, S.; Kugler, S.; Paw, Z.; Prokopowicz, A.; Shih, C.; Snow, R.; Young, E.; Cywin, C. Substituted 2H-isoquinolin-1-one as potent Rho-kinase inhibitors. part 1: hit-to-lead account. Bioorg. Med. Chem. Lett. 2010, 20, 32353239,  DOI: 10.1016/j.bmcl.2010.04.070
  293. 293
    Doe, C.; Bentley, R.; Behm, D. J.; Lafferty, R.; Stavenger, R.; Jung, D.; Bamford, M.; Panchal, T.; Grygielko, E.; Wright, L. L.; Smith, G. K.; Chen, Z.; Webb, C.; Khandekar, S.; Yi, T.; Kirkpatrick, R.; Dul, E.; Jolivette, L.; Marino, J. P.; Willette, R.; Lee, D.; Hu, E. J. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J. Pharmacol. Exp. Ther. 2007, 320, 8998,  DOI: 10.1124/jpet.106.110635
  294. 294
    Ginn, J. D.; Bosanac, T.; Chen, R.; Cywin, C.; Hickey, E.; Kashem, M.; Kerr, S.; Kugler, S.; Li, X.; Prokopowicz, A.; Schlyer, S.; Smith, J. D.; Turner, M. R.; Wu, F.; Young, E. R. Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats. Bioorg. Med. Chem. Lett. 2010, 20, 51535156,  DOI: 10.1016/j.bmcl.2010.07.014
  295. 295
    Li, R.; Martin, M. P.; Liu, Y.; Wang, B.; Patel, R. A.; Zhu, J. Y.; Sun, N.; Pireddu, R.; Lawrence, N. J.; Li, J.; Haura, E. B.; Sung, S. S.; Guida, W. C.; Schonbrunn, E.; Sebti, S. M. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem. 2012, 55, 24742478,  DOI: 10.1021/jm201289r
  296. 296
    Chen, Y. T.; Bannister, T. D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M. D.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 64066409,  DOI: 10.1016/j.bmcl.2008.10.080
  297. 297
    Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 64426446,  DOI: 10.1016/j.bmcl.2013.09.040
  298. 298
    Blangetti, M.; Rolando, B.; Marini, E.; Chegaev, K.; Guglielmo, S.; Lazzarato, L.; Lucarini, L.; Masini, E.; Fruttero, R. Gem-dinitroalkyl benzenes: a novel class of IOP-lowering agents for the treatment of ocular hypertension. ACS Med. Chem. Lett. 2017, 8, 10541059,  DOI: 10.1021/acsmedchemlett.7b00264
  299. 299
    Ehara, T.; Adams, C. M.; Bevan, D.; Ji, N.; Meredith, E. L.; Belanger, D. B.; Powers, J.; Kato, M.; Solovay, C.; Liu, D.; Capparelli, M.; Bolduc, P.; Grob, J. E.; Daniels, M. H.; Ferrara, L.; Yang, L.; Li, B.; Towler, C. S.; Stacy, R. C.; Prasanna, G.; Mogi, M. The discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a soluble guanylate cyclase activator specifically designed for topical ocular delivery as a therapy for glaucoma. J. Med. Chem. 2018, 61, 25522570,  DOI: 10.1021/acs.jmedchem.8b00007
  300. 300
    (a) May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin, M. A.; Sharif, N. A. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A potent peripherally acting 5-HT 2 receptor agonist with ocular hypertensive activity. J. Med. Chem. 2006, 49, 318328,  DOI: 10.1021/jm050663x .
    (b) May, J. A.; Chen, H. H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A. A novel and selective 5-HT 2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9 dihydropyrano[3,2-e]indole. J. Med. Chem. 2003, 46, 41884195,  DOI: 10.1021/jm030205t
  301. 301
    May, J. A.; Sharif, N. A.; McLaughlin, M. A.; Chen, H. H.; Severns, B. S.; Kelly, C. R.; Holt, W. F.; Young, R.; Glennon, R. A.; Hellberg, M. R.; Dean, T. R. Ocular hypotensive response in nonhuman primates of(8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a selective 5-HT2 receptor agonist. J. Med. Chem. 2015, 58, 88188833,  DOI: 10.1021/acs.jmedchem.5b00857
  302. 302
    Chemerovski-Glikman, M.; Mimouni, M.; Dagan, Y.; Haj, E.; Vainer, I.; Allon, R.; Blumenthal, E. Z.; Adler-Abramovich, L.; Segal, D.; Gazit, E.; Zayit-Soudry, S. Rosmarinic acid restores complete transparency of sonicated human cataract ex Vivo and delays cataract formation in Vivo. Sci. Rep. 2018, 8, 9341,  DOI: 10.1038/s41598-018-27516-9
  303. 303
    Chang, K. C.; Li, L.; Sanborn, T. M.; Shieh, B.; Lenhart, P.; Ammar, D.; LaBarbera, D. V.; Petrash, J. M. Characterization of emodin as a therapeutic agent for diabetic cataract. J. Nat. Prod. 2016, 79, 14391444,  DOI: 10.1021/acs.jnatprod.6b00185
  304. 304
    Da Settimo, F.; Primofiore, G.; La Motta, C.; Sartini, S.; Taliani, S.; Simorini, F.; Marini, A. M.; Lavecchia, A.; Novellino, E.; Boldrini, E. Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors. J. Med. Chem. 2005, 48, 68976907,  DOI: 10.1021/jm050382p
  305. 305
    Teufel, D. P.; Bennett, G.; Harrison, H.; van Rietschoten, K.; Pavan, S.; Stace, C.; Le Floch, F.; Van Bergen, T.; Vermassen, E.; Barbeaux, P.; Hu, T. T.; Feyen, J. H. M.; Vanhove, M. Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J. Med. Chem. 2018, 61, 28232836,  DOI: 10.1021/acs.jmedchem.7b01625
  306. 306
    (a) Inoue, T.; Morita, M.; Tojo, T.; Yoshihara, K.; Nagashima, A.; Moritomo, A.; Ohkubo, M.; Miyake, H. Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema. Bioorg. Med. Chem. 2013, 21, 12191233,  DOI: 10.1016/j.bmc.2012.12.025 .
    (b) Inoue, T.; Morita, M.; Tojo, T.; Nagashima, A.; Moritomo, A.; Miyake, H. S. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorg. Med. Chem. 2013, 21, 38733881,  DOI: 10.1016/j.bmc.2013.04.011
  307. 307
    González-Correa, J. A.; Rodríguez-Pérez, M. D.; Márquez-Estrada, L.; López-Villodres, J. A.; Reyes, J. J.; Rodriguez-Gutierrez, G.; Fernández-Bolaños, J.; De La Cruz, J. P. Neuroprotective effect of hydroxytyrosol in experimental diabetic retinopathy: relationship with cardiovascular biomarkers. J. Agric. Food Chem. 2018, 66, 637644,  DOI: 10.1021/acs.jafc.7b05063
  308. 308
    van Lier, J. E.; Tian, H.; Ali, H.; Cauchon, N.; Hasséssian, H. M. Trisulfonated porphyrazines: new photosensitizers for the treatment of retinal and subretinal edema. J. Med. Chem. 2009, 52, 41074110,  DOI: 10.1021/jm900350f
  309. 309
    Mores, A. M.; Casey, D.; Felix, C. M.; Phuan, P. W.; Verkman, A. S.; Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J. 2016, 30, 17891797,  DOI: 10.1096/fj.201500180
  310. 310
    Lee, S.; Phuan, P. W.; Felix, C. M.; Tan, J. A.; Levin, M. H.; Verkman, A. S. Nanomolar-potency aminophenyl-1,3,5-triazine activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel for prosecretory therapy of dry eye diseases. J. Med. Chem. 2017, 60, 12101218,  DOI: 10.1021/acs.jmedchem.6b01792
  311. 311
    Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci. 2003, 92, 20902097,  DOI: 10.1002/jps.10470
  312. 312
    Langhals, H.; Varja, A.; Laubichler, P.; Kernt, M.; Eibl, K.; Haritoglou, C. Cyanine dyes as optical contrast agents for ophthalmological surgery. J. Med. Chem. 2011, 54, 39033925,  DOI: 10.1021/jm2001986
  313. 313
    Myochin, T.; Hanaoka, K.; Komatsu, T.; Terai, T.; Nagano Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J. Am. Chem. Soc. 2012, 134, 1373013737,  DOI: 10.1021/ja303931b
  314. 314
    Simard, B.; Tomanek, B.; van Veggel, F. C.; Abulrob, A. Optimal dye-quencher pairs for the design of an ″activatable″ nanoprobe for optical imaging. Photochem. Photobiol. Sci. 2013, 12, 18241829,  DOI: 10.1039/c3pp50118c
  315. 315
    (a) Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharmacol. 2013, 2, 4764,  DOI: 10.5497/wjp.v2.i2.47 .
    (b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140146,  DOI: 10.1016/j.clindermatol.2014.10.006 .
    (c) Kim, Y. C.; Chiang, B.; Wu, X.; Prausnitz, M. R. Ocular delivery of macromolecules. J. Controlled Release 2014, 190, 172181,  DOI: 10.1016/j.jconrel.2014.06.043
  316. 316
    Eljarrat-Binstock, E.; Domb, A. J. Iontophoresis: a non-invasive ocular drug delivery. J. Controlled Release 2006, 110, 479489,  DOI: 10.1016/j.jconrel.2005.09.049
  317. 317
    Ye, T.; Yuan, K.; Zhang, W.; Song, S.; Chen, F.; Yang, X.; Wang, S.; Bi, J.; Pan, W. Prodrugs incorporated into nanotechnology-based drug delivery systems for possible improvement in bioavailability of ocular drugs delivery. Asian J. Pharm. Sci. 2013, 8, 207217,  DOI: 10.1016/j.ajps.2013.09.002
  318. 318
    Higashiyama, M.; Tajika, T.; Inada, K.; Ohtori, A. Improvement of the ocular bioavailability of carteolol by ion pair. J. Ocul. Pharmacol. Ther. 2006, 22, 333339,  DOI: 10.1089/jop.2006.22.333
  319. 319
    Loftssona, T.; Järvinen, T. Cyclodextrins in ophthalmic drug delivery. Adv. Drug Delivery Rev. 1999, 36, 5979,  DOI: 10.1016/S0169-409X(98)00055-6
  320. 320
    Lach, J. L.; Huang, H. S.; Schoenwald, R. D. Corneal penetration behavior of β-blocking agents II: assessment of barrier contributions. J. Pharm. Sci. 1983, 72, 12721279,  DOI: 10.1002/jps.2600721109
  321. 321
    Wang, J.; Zhao, F.; Liu, R.; Chen, J.; Zhang, Q.; Lao, R.; Wang, Z.; Jin, X.; Liu, C. Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies. Int. J. Nanomed. 2017, 12, 81158127,  DOI: 10.2147/IJN.S139436
  322. 322
    Huang, A.; Tseng, S.; Kenyon, K. Paracellular permeability of corneal and conjunctival epithelia. Invest. Ophth. Vis. Sc. 1989, 30, 684689
  323. 323
    Olsen, T. W.; Aaberg, S. Y.; Geroski, D. H.; Edelhauser, H. F. Human sclera: thickness and surface area. Am. J. Ophthalmol. 1998, 125, 237241,  DOI: 10.1016/S0002-9394(99)80096-8
  324. 324
    Cruysberg, L. P.; Nuijts, R. M.; Geroski, D. H.; Koole, L. H.; Hendrikse, F.; Edelhauser, H. F. In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J. Ocul. Pharmacol. Ther. 2002, 18, 559569,  DOI: 10.1089/108076802321021108
  325. 325
    Ambati, J.; Adamis, A. P. Transscleral drug delivery to the retina and choroid. Prog. Retinal Eye Res. 2002, 21, 145151,  DOI: 10.1016/S1350-9462(01)00018-0
  326. 326
    Maurice, D.; Polgar, J. Diffusion across the sclera. Exp. Eye Res. 1977, 25, 577582,  DOI: 10.1016/0014-4835(77)90136-1
  327. 327
    Ambati, J.; Canakis, C. S.; Miller, J. W.; Gragoudas, E. S.; Edwards, A.; Weissgold, D. J.; Kim, I.; Delori, F. C.; Adamis, A. P. Diffusion of high molecular weight compounds through sclera. Invest. Ophthal. Vis. Sci. 2000, 41, 11811185
  328. 328
    Pescina, S.; Govoni, P.; Antopolsky, M.; Murtomaki, L.; Padula, C.; Santi, P.; Nicoli, S. Permeation of proteins, oligonucleotide and dextrans across ocular tissues: experimental studies and a literature update. J. Pharm. Sci. 2015, 104, 21902202,  DOI: 10.1002/jps.24465
  329. 329
    Kamei, M.; Misono, K.; Lewis, H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am. J. Ophthalmol. 1999, 128, 739746,  DOI: 10.1016/S0002-9394(99)00239-1
  330. 330
    Jackson, T. L.; Antcliff, R. J.; Hillenkamp, J.; Marshall, J. Human retinal molecular weight exclusion limit and estimate of species variation. Invest. Ophthalmol. Visual Sci. 2003, 44, 21412146,  DOI: 10.1167/iovs.02-1027
  331. 331
    Marmor, M. F.; Negi, A.; Maurice, D. M. Kinetics of macromolecules injected into the subretinal space. Exp. Eye Res. 1985, 40, 687696,  DOI: 10.1016/0014-4835(85)90138-1
  332. 332
    Runkle, E. A.; Antonetti, D. A. The blood-retinal barrier: structure and functional significance. Methods Mol. Biol. 2011, 686, 133148,  DOI: 10.1007/978-1-60761-938-3_5
  333. 333
    Hammes, H. P.; Lin, J.; Renner, O.; Shani, M.; Lundqvist, A.; Betsholtz, C.; Brownlee, M.; Deutsch, U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51, 31073112,  DOI: 10.2337/diabetes.51.10.3107
  334. 334
    Motieju̅naitė, R.; Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 2008, 86, 171177,  DOI: 10.1016/j.exer.2007.10.013
  335. 335
    Pitkänen, L.; Ranta, V. P.; Moilanen, H.; Urtti, A. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest. Ophthalmol. Visual Sci. 2005, 46, 641646,  DOI: 10.1167/iovs.04-1051
  336. 336
    (a) Gaudana, R.; Ananthula, H. K.; Parenky, A.; Mitra, A. K. Ocular drug delivery. AAPS J. 2010, 12, 348360,  DOI: 10.1208/s12248-010-9183-3 .
    (b) Geroski, D. H.; Edelhauser, H. F. Drug delivery for posterior segment eye disease. Invest. Ophthalmol. Vis. Sci. 2000, 41, 961964.
    (c) Hornof, M.; Toropainen, E.; Urtti, A. cell culture models of the ocular barriers. Eur. J. Pharm. Biopharm. 2005, 60, 207225,  DOI: 10.1016/j.ejpb.2005.01.009
  337. 337
    (a) Boddu, S. H.; Gunda, S.; Earla, R.; Mitra, A. K. Ocular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eye. Bioanalysis 2010, 2, 487507,  DOI: 10.4155/bio.10.2 .
    (b) Kaur, I. P.; Kanwar, M. Ocular preparations: the formulation approach. Drug Dev. Ind. Pharm. 2002, 28, 473493,  DOI: 10.1081/DDC-120003445 .
    (c) Shirasaki, Y. Molecular design for enhancement of ocular penetration. J. Pharm. Sci. 2008, 97, 24622496,  DOI: 10.1002/jps.21200
  338. 338
    (a) She, S. C.; Steahly, L. P.; Moticka, E. J. Intracameral injection of allogeneic lymphocytes enhances corneal graft survival. Invest. Ophthalmol. Vis. Sci. 1990, 31, 19501956.
    (b) Lane, S. S.; Osher, R. H.; Masket, S.; Belani, S. Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgery. J. Cataract Refractive Surg. 2008, 34, 14511459,  DOI: 10.1016/j.jcrs.2008.05.034 .
    (c) Braga-Mele, R.; Chang, D. F.; Henderson, B. A.; Mamalis, N.; Talley-Rostov, A. Intracameral antibiotics: safety, efficacy, and preparation. J. Cataract Refractive Surg. 2014, 40, 21342142,  DOI: 10.1016/j.jcrs.2014.10.010
  339. 339
    (a) Duvvuri, S.; Majumdar, S.; Mitra, A. K. Drug delivery to the retina: challenges and opportunities. Expert Opin. Biol. Ther. 2003, 3, 4556,  DOI: 10.1517/14712598.3.1.45 .
    (b) Hsu, J. Drug delivery methods for posterior segment disease. Curr. Opin. Ophthalmol. 2007, 18, 235239,  DOI: 10.1097/ICU.0b013e3281108000 .
    (c) Holekamp, N. M. The vitreous gel: more than meets the eye. Am. J. Ophthalmol. 2010, 149, 3236,  DOI: 10.1016/j.ajo.2009.07.036
  340. 340
    (a) Hikichi, T.; Kado, M.; Yoshida, A. Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit. Retina 2000, 20, 195198,  DOI: 10.1097/00006982-200002000-00014 .
    (b) Martens, T. F.; Remaut, K.; Deschout, H.; Engbersen, J. F.; Hennink, W. E.; van Steenbergen, M. J.; Demeester, J.; De Smedt, S. C.; Braeckmans, K. Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy. J. Controlled Release 2015, 202, 8392,  DOI: 10.1016/j.jconrel.2015.01.030
  341. 341
    (a) Raghava, S.; Hammond, M.; Kompella, U. B. Periocular routes for retinal drug delivery. Expert Opin. Drug Delivery 2004, 1, 99114,  DOI: 10.1517/17425247.1.1.99 .
    (b) Janoria, K. G.; Gunda, S.; Boddu, S. H.; Mitra, A. K. Novel approaches to retinal drug delivery. Expert Opin. Drug Delivery 2007, 4, 371388,  DOI: 10.1517/17425247.4.4.371 .
    (c) Kim, S. H.; Galban, C. J.; Lutz, R. J.; Dedrick, R. L.; Csaky, K. G.; Lizak, M. J.; Wang, N. S.; Tansey, G.; Robinson, M. R. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging. Invest. Ophthalmol. Visual Sci. 2007, 48, 808814,  DOI: 10.1167/iovs.06-0670
  342. 342
    Hosoya, K. I.; Tomi, M. Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functions. Biol. Pharm. Bull. 2005, 28, 18,  DOI: 10.1248/bpb.28.1
  343. 343
    Stewart, P.; Tuor, U. Blood-eye barriers in the rat: correlation of ultrastructure with function. J. Comp. Neurol. 1994, 340, 566576,  DOI: 10.1002/cne.903400409
  344. 344
    Toda, R.; Kawazu, K.; Oyabu, M.; Miyazaki, T.; Kiuchi, Y. Comparison of drug permeabilities across the blood–retinal barrier, blood–aqueous humor barrier, and blood–brain barrier. J. Pharm. Sci. 2011, 100, 39043911,  DOI: 10.1002/jps.22610
  345. 345
    Farkouh, A.; Frigo, P.; Czejka, M. Systemic side effects of eye drop: a pharmacokinetic perspective. Clin. Ophthalmol. 2016, 10, 24332441,  DOI: 10.2147/OPTH.S118409
  346. 346
    Dellabella, A.; Andres, J. Ophthalmic toxicities of systemic drug therapy. US Pharm. 2015, 40, HS19HS24
  347. 347
    Epstein, D. L.; Grant, W. M. Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch. Ophthalmol. 1977, 95, 13781382,  DOI: 10.1001/archopht.1977.04450080088009
  348. 348
    Kim, J. H.; Kim, J. H.; Kim, K. W.; Kim, M. H.; Yu, Y. S. Intravenously administered gold nanoparticles pass through the blood–retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology 2009, 20, 505101,  DOI: 10.1088/0957-4484/20/50/505101
  349. 349
    Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423430,  DOI: 10.5650/jos.59.423
  350. 350
    Almeida, H.; Amaral, M. H.; Lobao, P.; Silva, A. C.; Loboa, J. M. Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerations. J. Pharm. Pharm. Sci. 2014, 17, 278293,  DOI: 10.18433/J3DP43
  351. 351
    (a) Battaglia, L.; Serpe, L.; Foglietta, F.; Muntoni, E.; Gallarate, M.; Del Pozo Rodriguez, A.; Solinis, M. A. Application of lipid nanoparticles to ocular drug delivery. Expert Opin. Drug Delivery 2016, 13, 17431757,  DOI: 10.1080/17425247.2016.1201059 .
    (b) Willem de Vries, J.; Schnichels, S.; Hurst, J.; Strudel, L.; Gruszka, A.; Kwak, M.; Bartz-Schmidt, K. U.; Spitzer, M. S.; Herrmann, A. DNA nanoparticles for ophthalmic drug delivery. Biomaterials 2018, 157, 98106,  DOI: 10.1016/j.biomaterials.2017.11.046 .
    (c) Silva, M. M.; Calado, R.; Marto, J.; Bettencourt, A.; Almeida, A. J.; Goncalves, L. M. D. Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administration. Mar. Drugs 2017, 15, 370,  DOI: 10.3390/md15120370 .
    (d) Alvarez-Trabado, J.; Diebold, Y.; Sanchez, A. Designing lipid nanoparticles for topical ocular drug delivery. Int. J. Pharm. 2017, 532, 204217,  DOI: 10.1016/j.ijpharm.2017.09.017 .
    (e) Almeida, H.; Amaral, M. H.; Lobao, P.; Frigerio, C.; Sousa Lobo, J. M. Nanoparticles in ocular drug delivery systems for topical administration: promises and challenges. Curr. Pharm. Des. 2015, 21, 52125224,  DOI: 10.2174/1381612821666150923095155 .
    (f) Janagam, D. R.; Wu, L.; Lowe, T. L. Nanoparticles for drug delivery to the anterior segment of the eye. Adv. Drug Delivery Rev. 2017, 122, 3164,  DOI: 10.1016/j.addr.2017.04.001
  352. 352
    (a) Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained drug release in nanomedicine: a long-acting nanocarrier-based formulation for glaucoma. ACS Nano 2014, 8, 419429,  DOI: 10.1021/nn4046024 .
    (b) Reimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M. Nanotherapies for the treatment of ocular diseases. Eur. J. Pharm. Biopharm. 2015, 95, 279293,  DOI: 10.1016/j.ejpb.2015.02.019
  353. 353
    (a) Kaur, I. P.; Garg, A.; Singla, A. K.; Aggarwal, D. Vesicular systems in ocular drug delivery: an overview. Int. J. Pharm. 2004, 269, 114,  DOI: 10.1016/j.ijpharm.2003.09.016 .
    (b) Sun, Y.; Fox, T.; Adhikary, G.; Kester, M.; Pearlman, E. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J. Leukocyte Biol. 2008, 83, 15121521,  DOI: 10.1189/jlb.0108076 .
    (c) Karn, P. R.; Kim, H. D.; Kang, H.; Sun, B. K.; Jin, S. E.; Hwang, S. J. Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion. Int. J. Nanomed. 2014, 9, 37913800,  DOI: 10.2147/IJN.S65601
  354. 354
    Shen, Y.; Tu, J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007, 9, E371,  DOI: 10.1208/aapsj0903044
  355. 355
    Abrishami, M.; Ghanavati, S. Z.; Soroush, D.; Rouhbakhsh, M.; Jaafari, M. R.; Malaekeh-Nikouei, B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 2009, 29, 699703,  DOI: 10.1097/IAE.0b013e3181a2f42a
  356. 356
    Sahoo, S. K.; Dilnawaz, F.; Krishnakumar, S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008, 13, 144151,  DOI: 10.1016/j.drudis.2007.10.021
  357. 357
    Ge, X.; Wei, M.; He, S.; Yuan, W. E. Advances of non-ionic surfactant vesicles (Niosomes) and their application in drug delivery. Pharmaceutics 2019, 11, 55,  DOI: 10.3390/pharmaceutics11020055
  358. 358
    Mukherjee, B.; Patra, B.; Layek, B.; Mukherjee, A. Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro study. Int. J. Nanomed. 2007, 2, 213225
  359. 359
    Vyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N. Discoidal niosome based controlled ocular delivery of timolol maleate. Pharmazie 1998, 53, 466499
  360. 360
    Aggarwal, D.; Kaur, I. P. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system. Int. J. Pharm. 2005, 290, 155159,  DOI: 10.1016/j.ijpharm.2004.10.026
  361. 361
    Kaur, I. P.; Smitha, R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev. Ind. Pharm. 2002, 28, 353369,  DOI: 10.1081/DDC-120002997
  362. 362
    (a) Gaafar, P. M.; Abdallah, O. Y.; Farid, R. M.; Abdelkader, H. Preparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisolone. J. Liposome Res. 2014, 24, 204215,  DOI: 10.3109/08982104.2014.881850 .
    (b) Abdelkader, H.; Ismail, S.; Kamal, A.; Alany, R. G. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J. Pharm. Sci. 2011, 100, 18331846,  DOI: 10.1002/jps.22422
  363. 363
    (a) Abdelbary, G.; El-Gendy, N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 2008, 9, 740747,  DOI: 10.1208/s12249-008-9105-1 .
    (b) Ali, Y.; Lehmussaari, K. Industrial perspective in ocular drug delivery. Adv. Drug Delivery Rev. 2006, 58, 12581268,  DOI: 10.1016/j.addr.2006.07.022
  364. 364
    Schaumberg, D. A.; Dana, R.; Buring, J. E.; Sullivan, D. A. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch. Ophthalmol. 2009, 127, 763768,  DOI: 10.1001/archophthalmol.2009.103
  365. 365
    Novelia®, 2015; https://www.nemera.net/products/ophthalmic/novelia/ (accessed 2019-01-21).
  366. 366
    (a) Introducing Ocusurf Nanostructured Emulsion as a 505(B)(2) Strategy; On Drug Delivery: Lewes, UK, 2016; https://www.ondrugdelivery.com/introducing-ocusurf-nanostructured-emulsion-505b2-strategy/ (accessed 2019-02-21).
    (b) Kompella, U. B.; Kadam, R. S.; Lee, V. Recent advances in ophthalmic drug delivery. Ther. Delivery 2010, 1, 435456,  DOI: 10.4155/tde.10.40
  367. 367
    Ophthalmic Drug Delivery; On Drug Delivery: Lewes, UK, 2020; https://www.ondrugdelivery.com/publications/63/emultech.pdf/ (accessed 2019-01-21).
  368. 368
    (a) Faulds, D.; Goa, K. L.; Benfield, P. Cyclosporin. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993, 45, 9531040,  DOI: 10.2165/00003495-199345060-00007 .
    (b) Opsisporin: A Long Acting Drug Delivery Approach. MidaTech Pharma; On Drug Delivery: Lewes, UK, 2016; https://pdfs.semanticscholar.org/30f3/4f4261c25f00edab736c69463dacae1bdc91.pdf/ (accessed 2019-05-21).
  369. 369
    Mandal, A.; Bisht, R.; Rupenthal, I. D.; Mitra, A. K. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J. Controlled Release 2017, 248, 96116,  DOI: 10.1016/j.jconrel.2017.01.012
  370. 370
    Yuan, X.; Marcano, D. C.; Shin, C. S.; Hua, X.; Isenhart, L. C.; Pflugfelder, S. C.; Acharya, G. Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano 2015, 9, 17491758,  DOI: 10.1021/nn506599f
  371. 371
    (a) Than, A.; Liu, C.; Chang, H.; Duong, P. K.; Cheung, C. M. G.; Xu, C.; Wang, X.; Chen, P. Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. Nat. Commun. 2018, 9, 4433,  DOI: 10.1038/s41467-018-06981-w .
    (b) Lowder, C. Y.; Hollander, D. A. Review of the drug-infused eye implant - ozurdex (dexamethasone intravitreal implant). US Ophthal. Rev. 2011, 4, 107112,  DOI: 10.17925/USOR.2011.04.02.107
  372. 372
    INVELTYS (Loteprednol Etabonate Ophthalmic Suspension) 1%; Kala Pharmaceuticals, 2019; https://inveltys.com/ (accessed 2020-03-20).
  373. 373
    Dextenza; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/dextenza/ (accessed 2020-03-20).
  374. 374
    (a) Kapoor, K. G.; Wagner, M. G.; Wagner, A. L. The sustained-release dexamethasone implant: expanding indications in vitreoretinal disease. Semin. Ophthalmol. 2015, 30, 475481,  DOI: 10.3109/08820538.2014.889179 .
    (b) London, N. J.; Chiang, A.; Haller, J. A. The dexamethasone drug delivery system: indications and evidence. Adv. Ther. 2011, 28, 351366,  DOI: 10.1007/s12325-011-0019-z
  375. 375
    Boyer, D. S.; Yoon, Y. H.; Belfort, R.; Bandello, F.; Maturi, R. K.; Augustin, A. J.; Li, X. Y.; Cui, H.; Hashad, Y.; Whitcup, S. M. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014, 121, 19041914,  DOI: 10.1016/j.ophtha.2014.04.024
  376. 376
    OZURDEX (Dexamethasone Intravitreal Implant), 2020; http://www.ozurdex.com/ (accessed Jan10, 2020).
  377. 377
    (a) Matonti, F.; Pommier, S.; Meyer, F.; Hajjar, C.; Merite, P. Y.; Parrat, E.; Rouhette, H.; Rebollo, O.; Guigou, S. Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur. J. Ophthalmol. 2016, 26, 454459,  DOI: 10.5301/ejo.5000787 .
    (b) Pareja-Ríos, A.; Ruiz-de la Fuente-Rodríguez, P.; Bonaque-González, S.; López-Gálvez, M.; Lozano-López, V.; Romero-Aroca, P. Intravitreal dexamethasone implants for diabetic macular edema. Int. J. Ophthalmol. 2018, 11, 7782,  DOI: 10.18240/ijo.2018.01.14 .
    (c) Iglicki, M.; Busch, C.; Zur, D.; Okada, M.; Mariussi, M.; Chhablani, J. K.; Cebeci, Z.; Fraser-Bell, S.; Chaikitmongkol, V.; Couturier, A.; Giancipoli, E.; Lupidi, M.; Rodríguez-Valdés, P. J.; Rehak, M.; Fung, A. T.; Goldstein, M.; Loewenstein, A. dexamethasone implant for diabetic macular edema in naïve compared with refractory eyes: The International Retina Group Real-Life 24 month multicenter study. the irgrel-dex study. Retina 2019, 39, 4451,  DOI: 10.1097/IAE.0000000000002196
  378. 378
    Menezo, M.; Roca, M.; Menezo, V.; Pascual, I. Intravitreal dexamethasone implant ozurdex® in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: A prospective 12-month followup study. Curr. Med. Res. Opin. 2019, 35, 21112116,  DOI: 10.1080/03007995.2019.1652449
  379. 379
    Errera, M. H.; Westcott, M.; Benesty, J.; Falah, S.; Smadja, J.; Orès, R.; Pratas, A. C.; Sedira, N.; Bensemlali, A.; Héron, E.; Goldschmidt, P.; Bodaghi, B.; Sahel, J. A. Comparison of the dexamethasone implant (ozurdex®) and inferior fornix-based sub-tenon yriamcinolone acetonide for treatment of inflammatory ocular diseases. Ocul. Immunol. Inflammation 2019, 27, 319329,  DOI: 10.1080/09273948.2018.1501492
  380. 380
    (a) Khurana, R. N.; Porco, T. C. Efficacy and safety of dexamethasone intravitreal implant for persistent uveitis cystoid macular edema. Retina 2015, 35, 16401646,  DOI: 10.1097/IAE.0000000000000515 .
    (b) Cao, J. H.; Mulvahill, M.; Zhang, L.; Joondeph, B. C.; Dacey, M. S. Dexamethasone intravitreal implant in the treatment of persistent uveitis macular edema in the absence of active inflammation. Ophthalmology 2014, 121, 18711876,  DOI: 10.1016/j.ophtha.2014.04.012 .
    (c) Bratton, M. L.; He, Y. G.; Weakley, D. R. Dexamethasone intravitreal implant (ozurdex) for the treatment of pediatric uveitis. J. AAPOS. 2014, 18, 110113,  DOI: 10.1016/j.jaapos.2013.11.014
  381. 381
    Ilhan, N.; Coskun, M.; Ilhan, O.; Tuzco, E. A.; Daglıoglu, M. C.; Elbeyli, A.; Keskin, U.; Oksuz, H. Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion. Cutaneous Ocul. Toxicol. 2015, 34, 294297,  DOI: 10.3109/15569527.2014.975242
  382. 382
    Güler, H. A.; Örnek, N.; Örnek, K.; Büyüktortop Gökçinar, N.; Oğurel, T.; Yumuşak, M. E.; Onaran, Z. Effect of dexamethasone intravitreal implant (Ozurdex®) on corneal endothelium in retinal vein occlusion patients. BMC Ophthalmol. 2018, 18, 235,  DOI: 10.1186/s12886-018-0905-0
  383. 383
    Phulke, S.; Kaushik, S.; Kaur, S.; Pandav, S. S. Steroid-induced glaucoma: an avoidable irreversible blindness. J. Curr. Glaucoma Pract. 2017, 11, 6772,  DOI: 10.5005/jp-journals-10028-1226
  384. 384
    Dot, C.; El Chehab, H.; Russo, A.; Agard, E. Ocular hypertension after intravitreal steroid injections: clinical update as of 2015. J. Fr. Ophtalmol. 2015, 38, 656664,  DOI: 10.1016/j.jfo.2015.03.002
  385. 385
    Sharma, A.; Kuppermann, B. D.; Bandello, F.; Lanzetta, P.; Zur, D.; Park, S. W.; Yu, H. G., Saravanan, V. R.; Zacharias, L. C.; Barreira, A. K.; Iglicki, M.; Miassi, F.; Veritti, D.; Tsao, S.; Makam, D.; Jain, N.; Loewenstein, A. Intraocular pressure (IOP) after intravitreal dexamethasone implant (ozurdex) amongst different geographic populations-geodex-iop study. Eye 2019,  DOI: 10.1038/s41433-019-0616-7 .
  386. 386
    Woodward, D. F.; Phelps, R. L.; Krauss, A. H.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A. Bimatoprost: a novel antiglaucoma agent. Cardiovasc. Drug Rev. 2004, 22, 103,  DOI: 10.1111/j.1527-3466.2004.tb00134.x
  387. 387
    (a) Eisenberg, D. L.; Toris, C. B.; Camras, C. B. Bimatoprost and travoprost: a review of recent studies of two new glaucoma drugs. Surv. Ophthalmol. 2002, 47, S105S115,  DOI: 10.1016/S0039-6257(02)00327-2 .
    (b) Orzalesi, N.; Rossetti, L.; Bottoli, A.; Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology 2006, 113, 239246,  DOI: 10.1016/j.ophtha.2005.10.045
  388. 388
    Kammer, J. A.; Katzman, B.; Ackerman, S.; Hollander, D. Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre study. Br. J. Ophthalmol. 2010, 94, 7479,  DOI: 10.1136/bjo.2009.158071
  389. 389
    Maulvi, F. A.; Soni, T. G.; Shah, D. O. A review on therapeutic contact lenses for ocular drug delivery. Drug Delivery 2016, 23, 30173026,  DOI: 10.3109/10717544.2016.1138342
  390. 390
    (a) Maulvi, F. A.; Soni, F. A.; Shah, D. O. Effect of timolol maleate concentration on uptake and release from hydrogel contact lenses using soaking method. J. Pharm. Appl. Sci. 2014, 1, 1723.
    (b) Carvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C. Sustained drug release by contact lenses for glaucoma treatment - a review. J. Controlled Release 2015, 202, 7682,  DOI: 10.1016/j.jconrel.2015.01.023 .
    (c) Guzman-Aranguez, A.; Colligris, B.; Pintor, J. Contact lenses: promising devices for ocular drug delivery. J. Ocul. Pharmacol. Ther. 2013, 29, 189199,  DOI: 10.1089/jop.2012.0212
  391. 391
    Xu, W.; Jiao, W.; Li, S.; Tao, X.; Mu, G. Bimatoprost loaded microemulsion laden contact lens to treat glaucoma. J. Drug Delivery Sci. Technol. 2019, 54, 101330,  DOI: 10.1016/j.jddst.2019.101330
  392. 392
    Yadav, M.; Guzman-Aranguez, A.; Perez de Lara, M. J.; Singh, M.; Singh, J.; Kaur, I. P. Bimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: in vitro and in vivo evaluation. Mater. Sci. Eng., C 2019, 103, 109730,  DOI: 10.1016/j.msec.2019.05.015
  393. 393
    Lee, S. S.; Hughes, P.; Ross, A. D.; Robinson, M. R. Biodegradable implants for sustained drug release in the eye. Pharm. Res. 2010, 27, 20432053,  DOI: 10.1007/s11095-010-0159-x
  394. 394
    Lewis, R. A.; Christie, W. C.; Day, D. G.; Craven, E. R.; Walters, T.; Bejanian, M.; Lee, S. S.; Goodkin, M. L.; Zhang, J.; Whitcup, S. M.; Robinson, M. R.; Aung, T.; Beck, A. D.; Christie, W. C.; Coote, M.; Crane, C. J.; Craven, E. R.; Crichton, A.; Day, D. G.; Durcan, F. J.; Flynn, W. J.; Gagne, S.; Goldberg, D. F.; Jinapriya, D.; Johnson, C. S.; Kurtz, S.; Lewis, R. A.; Mansberger, S. L.; Perera, S. A.; Rotberg, M. H.; Saltzmann, R. M.; Schenker, H. I.; Tepedino, M. E.; Yap-Veloso, M. I. R.; Uy, H. S.; Walters, T. R. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am. J. Ophthalmol. 2017, 175, 137147,  DOI: 10.1016/j.ajo.2016.11.020
  395. 395
    Lee, S. S.; Dibas, M.; Almazan, A.; Robinson, M. R. Dose–response of intracameral bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure. J. Ocul. Pharmacol. Ther. 2019, 35, 138144,  DOI: 10.1089/jop.2018.0095
  396. 396
    Seal, J. R.; Robinson, M. R.; Burke, J.; Bejanian, M.; Coote, M.; Attar, M. Intracameral sustained-release bimatoprost implant delivers bimatoprost to target tissues with reduced drug exposure to off-target tissues. J. Ocul. Pharmacol. Ther. 2019, 35, 5057,  DOI: 10.1089/jop.2018.0067
  397. 397
    U.S. FDA Accepts Allergan’s New Drug Application for Bimatoprost Sustained-Release in Patients with Open-Angle Glaucoma or Ocular Hypertension; U.S. Food and Drug Administration, 2019; https://www.prnewswire.com/news-releases/us-fda-accepts-allergans-new-drug-application-for-bimatoprost-sustained-release-in-patients-with-open-angle-glaucoma-or-ocular-hypertension-300886238.html (accessed Dec 19, 2019).
  398. 398
    (a) Jervis, L. P. A summary of recent advances in ocular inserts and implants. J. Bioequivalence Bioavailability 2016, 9, 320323,  DOI: 10.4172/jbb.1000318 .
    (b) Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602624,  DOI: 10.1124/jpet.119.256933 .
    (c) Gote, V.; Pal, D. Ocular implants in the clinic and under clinical investigation for ocular disorders. EC Opthalmol. 2019, 10.8, 660666

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  • Abstract

    Figure 1

    Figure 1. Anatomy of eye.

    Figure 2

    Figure 2. (a) Retina diagram by optical coherence tomography: normal retina (top) and a retina with pigmented epithelium detachment (bottom). (b) Normal retina and macula. (c) Macula with confluent soft drusen. (d) Macula of geographic atrophy. (e) Macula (CNV) with hemorrhage. (f) Optic nerve with glaucomatous excavation.(4) Reproduced with permission from ref (4). Copyright 2012 Nature Research.

    Figure 3

    Figure 3. Mechanism of action: visual cycle inhibitors.

    Figure 4

    Figure 4. Conventional pathway for aqueous humor.

    Figure 5

    Figure 5. Rock and LIM kinase inhibition.(109) Adapted with permission from ref (109). Copyright 2016 American Chemical Society.

    Figure 6

    Figure 6. ROCK inhibitors.(124−134)

    Figure 7

    Figure 7. Netarsudil as prodrug.

    Figure 8

    Figure 8. Signaling cascade for AR agonist and antagonist.(109) Adapted with permission from ref (109). Copyright 2016 American Chemical Society.

    Figure 9

    Figure 9. LBN and NO derivatives of prostaglandins.

    Figure 10

    Figure 10. LIM kinase inhibitors and EP2 receptor agonists

    Figure 11

    Figure 11. VP-101 as a promising compound that improved lens transparency.

    Figure 12

    Figure 12. Fenretinide derivatives.

    Figure 13

    Figure 13. Non-retinoid based RBP4 antagonist.

    Figure 14

    Figure 14. RBP4 antagonists.

    Figure 15

    Figure 15. RBP4 ligands.

    Figure 16

    Figure 16. Complement pathway inhibitors.

    Figure 17

    Figure 17. Complement pathway inhibitors.

    Figure 18

    Figure 18. Complement pathway inhibitors.

    Figure 19

    Figure 19. Complement pathway inhibitors.

    Figure 20

    Figure 20. Complement pathway inhibitors.

    Figure 21

    Figure 21. VEGFR-2 inhibitor.

    Figure 22

    Figure 22. VEGFR-2 inhibitors

    Figure 23

    Figure 23. Homoisoflavanoid analogues.

    Figure 24

    Figure 24. Benzotriazine-based compounds.

    Figure 25

    Figure 25. Prodrug of haloperidol metabolite II.

    Figure 26

    Figure 26. sst2 agonists.

    Figure 27

    Figure 27. HIF-1 α inhibitors.

    Figure 28

    Figure 28. Multifunctional antioxidant as potential ocular therapeutics.

    Figure 29

    Figure 29. Inhibitors of A2E photooxidation, hypocrellin derivatives as photosensitizers for photodynamic therapy.

    Figure 30

    Figure 30. CA inhibitors.

    Figure 31

    Figure 31. Monothiocarbamates as CA inhibitor.

    Figure 32

    Figure 32. CA inhibitors.

    Figure 33

    Figure 33. CA inhibitors.

    Figure 34

    Figure 34. CA inhibitors.

    Figure 35

    Figure 35. Benzenesulfonamides bearing phenyl-1,2,3-triazole moieties.

    Figure 36

    Figure 36. Hybrid scaffolds as antiglaucoma drugs.

    Figure 37

    Figure 37. CA inhibitors.

    Figure 38

    Figure 38. ROCK II inhibitors.

    Figure 39

    Figure 39. Tetrahydroisoquinolines as ROCK inhibitors.

    Figure 40

    Figure 40. Isoquinoline-based ROCK inhibitors.

    Figure 41

    Figure 41. Rock inhibitors.

    Figure 42

    Figure 42. LIM-Kinase and ROCK inhibitors.

    Figure 43

    Figure 43. gem-Dinitroalkyl benzenes as IOP lowering agents.

    Figure 44

    Figure 44. Compounds for topical ocular administration.

    Figure 45

    Figure 45. Selective EP2 receptor agonist.

    Figure 46

    Figure 46. 5-HT 2 receptor agonists

    Figure 47

    Figure 47. Rosmarinic acid as a potent cataract modulator.

    Figure 48

    Figure 48. Emodin as aldose reductase inhibitor.

    Figure 49

    Figure 49. Naphtho[1,2-d]isothiazole as aldose reductase inhibitors.

    Figure 50

    Figure 50. Plasma kallikrein inhibitors.

    Figure 51

    Figure 51. Thiazole derivatives as potent VAP-1 inhibitors.

    Figure 52

    Figure 52. Hydroxytyrosol and mononaphthotrisulfobenzoporphyrazines photosensitizers.

    Figure 53

    Figure 53. CFTR activators.

    Figure 54

    Figure 54. Cyanine dyes.

    Figure 55

    Figure 55. Hypoxia responsive molecular optical fluorescence imaging probe.

    Figure 56

    Figure 56. Physicochemical properties of drugs affecting ODD.

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 398 other publications.

    1. 1
      (a) Graw, J. Eye development. Curr. Top. Dev. Biol. 2010, 90, 343386,  DOI: 10.1016/S0070-2153(10)90010-0 .
      (b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140146,  DOI: 10.1016/j.clindermatol.2014.10.006
    2. 2
      Awwad, S.; Mohamed Ahmed, A. H.; Sharma, G.; Heng, J. S.; Khaw, P. T.; Brocchini, S.; Lockwood, A. Principles of pharmacology in the eye. Br. J. Pharmacol. 2017, 174, 42054223,  DOI: 10.1111/bph.14024
    3. 3
      Clark, A. F.; Yorio, T. Ophthalmic drug discovery. Nat. Rev. Drug Discovery 2003, 2, 448459,  DOI: 10.1038/nrd1106
    4. 4
      Zhang, K.; Zhang, L.; Weinreb, R. N. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat. Rev. Drug Discovery 2012, 11, 541559,  DOI: 10.1038/nrd3745
    5. 5
      Zhang, J.; Tuo, J.; Wang, Z.; Zhu, A.; Machalińska, A.; Long, Q. Pathogenesis of common ocular diseases. J. Ophthalmol. 2015, 2015, 734527,  DOI: 10.1155/2015/734527
    6. 6
      Blindness and Vision Impairment; World Health Organization, 2019; https://www.who.int/blindness/en/ (accessed 2019-03-29).
    7. 7
      Sturdivant, J. M.; Royalty, S. M.; Lin, C. W.; Moore, L. A.; Yingling, J. D.; Laethem, C. L.; Sherman, B.; Heintzelman, G. R.; Kopczynski, C. C.; deLong, M. A. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg. Med. Chem. Lett. 2016, 26, 24752480,  DOI: 10.1016/j.bmcl.2016.03.104
    8. 8
      Impagnatiello, F.; Bastia, E.; Almirante, N.; Brambilla, S.; Duquesroix, B.; Kothe, A. C.; Bergamini, M. V. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br. J. Pharmacol. 2019, 176, 10791089,  DOI: 10.1111/bph.14328
    9. 9
      Abidi, A.; Shukla, P.; Ahmad, A. Lifitegrast: a novel drug for treatment of dry eye disease. J. Pharmacol. Pharmacother. 2016, 7, 194198,  DOI: 10.4103/0976-500X.195920
    10. 10
      Mehran, N. A.; Sinha, S.; Razeghinejad, R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost. Eye 2020, 34, 7288,  DOI: 10.1038/s41433-019-0671-0
    11. 11
      Lewis, R. A.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339344,  DOI: 10.1136/bjophthalmol-2015-306778
    12. 12
      Patel, U.; Boucher, M.; de Léséleuc, L.; Visintini, S. Voretigene neparvovec: an emerging gene therapy for the treatment of inherited blindness. CADTH Issues in Emerging Health Technologies 2018, 169, 311
    13. 13
      ReSure Sealant; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/resure-sealant/ (accessed 2020-03-05).
    14. 14
      Dugel, P. U.; Koh, A.; Ogura, Y.; Jaffe, G. J.; Schmidt-Erfurth, U.; Brown, D. M.; Gomes, A. V.; Warburton, J.; Weichselberger, A.; Holz, F. G. Hawk and harrier: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2020, 127, 7284,  DOI: 10.1016/j.ophtha.2019.04.017
    15. 15
      (a) Khan, S.; Warade, S.; Singhavi, D. J. Improvement in ocular bioavailability and prolonged delivery of tobramycin sulfate following topical ophthalmic administration of drug-loaded mucoadhesive microparticles incorporated in thermosensitive in situ gel. J. Ocul. Pharmacol. Ther. 2018, 34, 287297,  DOI: 10.1089/jop.2017.0079 .
      (b) Garty, S.; Shirakawa, R.; Warsen, A.; Anderson, E. M.; Noble, M. L.; Bryers, J. D.; Ratner, B. D.; Shen, T. T. Sustained antibiotic release from an intraocular lens-hydrogel assembly for cataract surgery. Invest. Ophthalmol. Visual Sci. 2011, 52, 61096116,  DOI: 10.1167/iovs.10-6071 .
      (c) Foureaux, G.; Franca, J. R.; Nogueira, J. C.; de Oliveira Fulgencio, G.; Ribeiro, T. G.; Castilho, R. O.; Yoshida, M. I.; Fuscaldi, L. L.; Fernandes, S. O.; Cardoso, V. N.; Cronemberger, S.; Faraco, A. A.; Ferreira, A. J. Ocular inserts for sustained release of the angiotensin-converting enzyme 2 activator, diminazene aceturate, to treat glaucoma in rats. PLoS One 2015, 10, e0133149,  DOI: 10.1371/journal.pone.0133149 .
      (d) Khurana, G.; Arora, S.; Pawar, P. K. Ocular insert for sustained delivery of gatifloxacin sesquihydrate: preparation and evaluations. Int. J. Pharm. Invest. 2012, 2, 7077,  DOI: 10.4103/2230-973X.100040 .
      (e) Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423430,  DOI: 10.5650/jos.59.423 .
      (f) Sieg, J. W.; Robinson, J. R. Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments. J. Pharm. Sci. 1979, 68, 724728,  DOI: 10.1002/jps.2600680619 .
      (g) Newton, D. W.; Becker, C. H.; Torosian, G. Physical and chemical characteristics of water-soluble, semisolid, anhydrous bases for possible ophthalmic use. J. Pharm. Sci. 1973, 62 (9), 15381542,  DOI: 10.1002/jps.2600620936 .
      (h) Ludwig, A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Delivery Rev. 2005, 57, 15951639,  DOI: 10.1016/j.addr.2005.07.005
    16. 16
      Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602624,  DOI: 10.1124/jpet.119.256933
    17. 17
      (a) Kortesuo, P.; Ahola, M.; Karlsson, S.; Kangasniemi, I.; Yli-Urpo, A.; Kiesvaara, J. P. Silica xerogel as an implantable carrier for controlled drug delivery-evaluation of drug distribution and tissue effects after implantation. Biomaterials 2000, 21, 193198,  DOI: 10.1016/S0142-9612(99)00148-9 .
      (b) Jokinen, M.; Koskinen, M.; Areva, S. Rationale of using conventional sol-gel derived SiO2 for delivery of biologically active agents. Key Eng. Mater. 2008, 377, 195210,  DOI: 10.4028/www.scientific.net/KEM.377.195
    18. 18
      (a) Phan, C. M.; Subbaraman, L. N.; Jones, L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye Contact Lens 2013, 39, 162168,  DOI: 10.1097/ICL.0b013e31827a7a07 .
      (b) Peng, C. C.; Kim, J. A.; Chauhan, A. Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing vitamin E diffusion barriers. Biomaterials 2010, 31, 40324047,  DOI: 10.1016/j.biomaterials.2010.01.113
    19. 19
      Bochot, A.; Fattal, E. Liposomes for intravitreal drug delivery: a state of the art. J. Controlled Release 2012, 161, 628634,  DOI: 10.1016/j.jconrel.2012.01.019
    20. 20
      Hong, C. H.; Arosemena, A.; Zurakowski, D.; Ayyala, R. S. Glaucoma drainage devices: a systematic literature review and current controversies. Surv. Ophthalmol. 2005, 50, 4860,  DOI: 10.1016/j.survophthal.2004.10.006
    21. 21
      Tseng, C. L.; Chen, K. H.; Su, W. Y.; Lee, Y. H.; Wu, C. C.; Lin, F. H. Cationic gelatin nanoparticles for drug delivery to the ocular surface: in vitro and in vivo evaluation. J. Nano. 2013, 2013, 238351,  DOI: 10.1155/2013/238351
    22. 22
      Ophthalmic Drug Delivery; Frederick Furness Publishing Ltd: Lewes, UK, 2019; https://www.ondrugdelivery.com/publications/63/ForSight.pdf/ (accessed 2019-01-24).
    23. 23
      Nocentini, A.; Ceruso, M.; Bua, S.; Lomelino, C. L.; Andring, J. T.; McKenna, R.; Lanzi, C.; Sgambellone, S.; Pecori, R.; Matucci, R.; Filippi, L.; Gratteri, P.; Carta, F.; Masini, E.; Selleri, S.; Supuran, C. T. Discovery of β-adrenergic receptors blocker-carbonic anhydrase inhibitor hybrids for multitargeted antiglaucoma therapy. J. Med. Chem. 2018, 61, 53805394,  DOI: 10.1021/acs.jmedchem.8b00625
    24. 24
      Cioffi, C. L.; Racz, B.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Dobri, N.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Bicyclic [3.3. 0]-octahydrocyclopenta [c] pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2015, 58, 58635888,  DOI: 10.1021/acs.jmedchem.5b00423
    25. 25
      Uddin, M. I.; Evans, S. M.; Craft, J. R.; Marnett, L. J.; Uddin, M. J.; Jayagopal, A. Applications of azo-based probes for imaging retinal hypoxia. ACS Med. Chem. Lett. 2015, 6, 445449,  DOI: 10.1021/ml5005206
    26. 26
      Maibaum, J.; Liao, S. M.; Vulpetti, A.; Ostermann, N.; Randl, S.; Rüdisser, S.; Lorthiois, E.; Erbel, P.; Kinzel, B.; Kolb, F.; Barbieri, S.; Wagner, J.; Durand, C.; Fettis, K.; Dussauge, S.; Hughes, N.; Delgado, O.; Hommel, U.; Gould, T.; Mac Sweeney, A.; Gerhartz, B.; Cumin, F.; Flohr, S.; Schubart, A.; Jaffee, B.; Harrison, R.; Risitano, A. M.; Eder, J.; Anderson, K. A small-molecule factor D inhibitors targeting the alternative complement pathway. Nat. Chem. Biol. 2016, 12, 11051110,  DOI: 10.1038/nchembio.2208
    27. 27
      Vulpetti, A.; Randl, S.; Rudisser, S.; Ostermann, N.; Erbel, P.; Mac Sweeney, A.; Zoller, T.; Salem, B.; Gerhartz, B.; Cumin, F.; Hommel, U.; Dalvit, C.; Lorthiois, E.; Maibaum, J. Structure-based library design and fragment screening for the identification of reversible complement factor D protease inhibitors. J. Med. Chem. 2017, 60, 19461958,  DOI: 10.1021/acs.jmedchem.6b01684
    28. 28
      Lorthiois, E.; Anderson, K.; Vulpetti, A.; Rogel, O.; Cumin, F.; Ostermann, N.; Steinbacher, S.; Mac Sweeney, A.; Delgado, O.; Liao, S.-M.; Randl, S.; Rüdisser, S.; Dussauge, S.; Fettis, K.; Kieffer, L.; de Erkenez, A.; Yang, L.; Hartwieg, C.; Argikar, U. A.; La Bonte, L. R.; Newton, R.; Kansara, V.; Flohr, S.; Hommel, U.; Jaffee, B.; Maibaum, J. Discovery of highly potent and selective small-molecule reversible factor D inhibitors demonstrating alternative complement pathway inhibition in vivo. J. Med. Chem. 2017, 60, 57175735,  DOI: 10.1021/acs.jmedchem.7b00425
    29. 29
      Jendza, K.; Kato, M.; Salcius, M.; Srinivas, H.; De Erkenez, A.; Nguyen, A.; McLaughlin, D.; Be, C.; Wiesmann, C.; Murphy, J.; Bolduc, P.; Mogi, M.; Duca, J.; Namil, A.; Capparelli, M.; Darsigny, V.; Meredith, E.; Tichkule, R.; Ferrara, L.; Heyder, J.; Liu, F.; Horton, P. A.; Romanowski, M. J.; Schirle, M.; Mainolfi, N.; Anderson, K.; Michaud, G. A. A small-molecule inhibitor of C5 complement protein. Nat. Chem. Biol. 2019, 15, 666668,  DOI: 10.1038/s41589-019-0303-9
    30. 30
      Karki, R.; Powers, J.; Mainolfi, N.; Anderson, K.; Belanger, D. B.; Liu, D.; Ji, N.; Jendza, K.; Gelin, C. F.; Mac Sweeney, A.; Solovay, C.; Delgado, O.; Crowley, M.; Liao, S. M.; Argikar, U. A.; Flohr, S.; La Bonte, L. R.; Lorthiois, E. L.; Vulpetti, A.; Brown, A.; Long, D.; Prentiss, M.; Gradoux, N.; de Erkenez, A.; Cumin, F.; Adams, C.; Jaffee, B.; Mogi, M. Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway. J. Med. Chem. 2019, 62, 46564668,  DOI: 10.1021/acs.jmedchem.9b00271
    31. 31
      Haddad, S.; Chen, C. A.; Santangelo, S. L.; Seddon, J. M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 2006, 51, 316363,  DOI: 10.1016/j.survophthal.2006.05.001
    32. 32
      Rattner, A.; Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nat. Rev. Neurosci. 2006, 7, 860872,  DOI: 10.1038/nrn2007
    33. 33
      Chou, R.; Dana, T.; Bougatsos, C.; Grusing, S.; Blazina, I. Screening for impaired visual acuity in older adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016, 315, 915933,  DOI: 10.1001/jama.2016.0783
    34. 34
      Leibowitz, H. M.; Krueger, D. E.; Maunder, L. R.; Milton, R. C.; Kini, M. M.; Kahn, H. A.; Nickerson, R. J.; Pool, J.; Colton, T. L.; Ganley, J. I.; Loewenstein, T. R. The framingham eye study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973 −1975. Surv. Ophthalmol. 1980, 24, 335610,  DOI: 10.1016/0039-6257(80)90015-6
    35. 35
      Wong, W. L.; Su, X.; Li, X.; Cheung, C. M.; Klein, R.; Cheng, C. Y.; Wong, T. Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e10616,  DOI: 10.1016/S2214-109X(13)70145-1
    36. 36
      Maller, J.; George, S.; Purcell, S.; Fagerness, J.; Altshuler, D.; Daly, M. J.; Seddon, J. M. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 2006, 38, 10551059,  DOI: 10.1038/ng1873
    37. 37
      Klein, M. L.; Schultz, D. W.; Edwards, A.; Matise, T. C.; Rust, K.; Berselli, C. B.; Trzupek, K.; Weleber, R. G.; Ott, J.; Wirtz, M. K.; Acott, T. S. Age-related macular degeneration. clinical features in a large family and linkage to chromosome 1q. Arch. Ophthalmol. 1998, 116, 10821088,  DOI: 10.1001/archopht.116.8.1082
    38. 38
      Mitchell, P.; Wang, J. J.; Smith, W.; Leeder, S. R. Smoking and the 5-year incidence of age-related maculopathy: the blue mountains eye study. Arch. Ophthalmol. 2002, 120, 13571363,  DOI: 10.1001/archopht.120.10.1357
    39. 39
      Mitchell, P.; Liew, G.; Gopinath, B.; Wong, T. Y. Age-related macular degeneration. Lancet 2018, 392, 11471159,  DOI: 10.1016/S0140-6736(18)31550-2
    40. 40
      Crabb, J. W.; Miyagi, M.; Gu, X.; Shadrach, K.; West, K. A.; Sakaguchi, H.; Kamei, M.; Hasan, A.; Yan, L.; Rayborn, M. E.; Salomon, R. G.; Hollyfield, J. G. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1468214687,  DOI: 10.1073/pnas.222551899
    41. 41
      (a) Okubo, A.; Rosa, R. H.; Bunce, C. V.; Alexander, R. A.; Fan, J. T.; Bird, A. C.; Luthert, P. J. The relationships of age changes in retinal pigment epithelium and bruch’s membrane. Invest. Ophthalmol. Vis. Sci. 1999, 40, 443449.
      (b) Green, W. R.; McDonnell, P. J.; Yeo, J. H. Pathologic features of senile macular degeneration. Ophthalmology 1985, 92, 615627,  DOI: 10.1016/S0161-6420(85)33993-3
    42. 42
      Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat. Med. 2010, 16, 11071111,  DOI: 10.1038/nm1010-1107
    43. 43
      (a) Macular Degeneration Treatments; American Macular Degeneration Foundation: Northampton, MA. 2019; https://www.macular.org/treatments/ (accessed 2019-05-15).
      (b) Anti-VEGF Treatment; Royal National Institute of Blind People: London, 2019; https://www.rnib.org.uk/eye-health/eye-conditions/anti-vegf-treatment/ (accessed 2019-01-15).
    44. 44
      (a) Martin, D. F.; Maguire, M. G.; Ying, G. S.; Grunwald, J. E.; Fine, S. L.; Jaffe, G. J. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2011, 364, 18971908,  DOI: 10.1056/NEJMoa1102673 .
      (b) Aflibercept; DrugBank, 2019; https://www.drugbank.ca/drugs/DB08885/ (accessed 2019-01-17).
    45. 45
      Williams, M. A.; McKay, G. J.; Chakravarthy, U. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst. Rev. 2014, 15, CD009300,  DOI: 10.1002/14651858.CD009300.pub2
    46. 46
      Khandhadia, S.; Cipriani, V.; Yates, J. R.; Lotery, A. J. Age-related macular degeneration and the complement system. Immunobiology 2012, 217, 127146,  DOI: 10.1016/j.imbio.2011.07.019
    47. 47
      (a) Katz, M. L.; Robison, W. G. What is lipofuscin? defining characteristics and differentiation from other autofluorescent lysosomal storage bodies. Arch. Gerontol. Geriatr. 2002, 34, 169184,  DOI: 10.1016/S0167-4943(02)00005-5 .
      (b) Lamb, L. E.; Simon, J. D. A2E: a component of ocular lipofuscin. Photochem. Photobiol. 2004, 79, 127136,  DOI: 10.1111/j.1751-1097.2004.tb00002.x .
      (c) Iriyama, A.; Inoue, Y.; Takahashi, H.; Tamaki, Y.; Jang, W. D.; Yanagi, Y. A2E, a component of lipofuscin, is pro-angiogenic in vivo. J. Cell. Physiol. 2009, 220, 469475,  DOI: 10.1002/jcp.21792
    48. 48
      (a) Kanai, M.; Raz, A.; Goodman, D. S. Retinol-binding protein: the transport protein for vitamin A in human plasma. J. Clin. Invest. 1968, 47, 20252044,  DOI: 10.1172/JCI105889 .
      (b) Naylor, H. M.; Newcomer, M. E. The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP. Biochemistry 1999, 38, 26472653,  DOI: 10.1021/bi982291i
    49. 49
      Hussain, R. M.; Gregori, N. Z.; Ciulla, T. A.; Lam, B. L. Pharmacotherapy of retinal disease with visual cycle modulators. Expert Opin. Pharmacother. 2018, 19, 471481,  DOI: 10.1080/14656566.2018.1448060
    50. 50
      (a) Johnson, S. C.; Rabinovitch, P. S.; Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493, 338345,  DOI: 10.1038/nature11861 .
      (b) Park, T. K.; Lee, S. H.; Choi, J. S.; Nah, S. K.; Kim, H. J.; Park, H. Y.; Lee, H.; Lee, S. H. S.; Park, K. Adeno-associated viral vector-mediated mTOR inhibition by short hairpin RNA suppresses laser-induced choroidal neovascularization. Mol. Ther.--Nucleic Acids 2017, 8, 2635,  DOI: 10.1016/j.omtn.2017.05.012
    51. 51
      Singh, M. S.; MacLaren, R. E. Stem cell treatment for age-related macular degeneration: the challenges. Invest. Ophthalmol. Visual Sci. 2018, 59, AMD78AMD82,  DOI: 10.1167/iovs.18-24426
    52. 52
      Macular Degeneration; International Society for Stem Cell Research. 2019; https://www.closerlookatstemcells.org/stem-cells-medicine/macular-degeneration/ (accessed 2019-03-17).
    53. 53
      Villanueva, M. T. A stem-cell-derived eye patch for macular degeneration. Nat. Rev. Drug Discovery 2019, 18, 172,  DOI: 10.1038/d41573-019-00017-8
    54. 54
      Moore, N. A.; Bracha, P.; Hussain, R. M.; Morral, N.; Ciulla, T. A. Gene therapy for age-related macular degeneration. Expert Opin. Biol. Ther. 2017, 17, 12351244,  DOI: 10.1080/14712598.2017.1356817
    55. 55
      Bainbridge, J. W.; Smith, A. J.; Barker, S. S.; Robbie, S.; Henderson, R.; Balaggan, K.; Viswanathan, A.; Holder, G. E.; Stockman, A.; Tyler, N.; Petersen-Jones, S.; Bhattacharya, S. S.; Thrasher, A. J.; Fitzke, F. W.; Carter, B. J.; Rubin, G. S.; Moore, A. T.; Ali, R. R. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 2008, 358, 22312239,  DOI: 10.1056/NEJMoa0802268
    56. 56
      European Commission Approves Spark Therapeutics; Spark Therapeutics, 2019; http://ir.sparktx.com/news-releases/news-release-details/european-commission-approves-spark-therapeutics-luxturnar/ (accessed 2019-03-19).
    57. 57
      Gordon, K.; Del Medico, A.; Sander, I.; Kumar, A.; Hamad, B. Gene therapies in ophthalmic disease. Nat. Rev. Drug Discovery 2019, 18, 415416,  DOI: 10.1038/d41573-018-00016-1
    58. 58
      Constable, I. J.; Lai, C. M.; Magno, A. L.; French, M. A.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Degli-Esposti, M. A.; Rakoczy, E. P. Gene therapy in neovascular age-related macular degeneration: three-year follow-up of a phase 1 randomized dose escalation trial. Am. J. Ophthalmol. 2017, 177, 150158,  DOI: 10.1016/j.ajo.2017.02.018
    59. 59
      Bordet, T.; Behar-Cohen, F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discovery Today 2019, 24, 16851693,  DOI: 10.1016/j.drudis.2019.05.038
    60. 60
      Campochiaro, P. A.; Nguyen, Q. D.; Shah, S. M.; Klein, M. L.; Holz, E.; Frank, R. N.; Saperstein, D. A.; Gupta, A.; Stout, J. T.; Macko, J.; DiBartolomeo, R.; Wei, L. L. Adenoviral vector delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum. Gene Ther. 2006, 17, 167176,  DOI: 10.1089/hum.2006.17.167
    61. 61
      Rakoczy, E. P.; Lai, C. M.; Magno, A. L.; Wikstrom, M. E.; French, M. A.; Pierce, C. M.; Schwartz, S. D.; Blumenkranz, M. S.; Chalberg, T. W.; Degli-Esposti, M. A.; Constable, I. J. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1-year follow-up of a phase 1 randomised clinical trial. Lancet 2015, 386, 23952403,  DOI: 10.1016/S0140-6736(15)00345-1
    62. 62
      Avalanche Biotechnologies, Inc., Announces Positive Top-Line Phase 2a Results for Ava-101 in Wet Age-Related Macular Degeneration; Adverum Biotechnologies, 2019; http://investors.adverum.com/news-releases/newsrelease-details/avalanche-biotechnologies-inc-announces-positivetop-line-phase/ (accessed 2019-12-10).
    63. 63
      Constable, I. J.; Pierce, C. M.; Lai, C. M.; Magno, A. L.; Degli-Esposti, M. A.; French, M. A.; McAllister, I. A.; Butler, S.; Barone, S. B.; Schwartz, S. D.; Blumenkranz, M. S.; Rakoczy, E. P. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine 2016, 14, 168175,  DOI: 10.1016/j.ebiom.2016.11.016
    64. 64
      Scaria, A. L.; LeHalpere, A.; Purvis, A.; delacono, C.; Cheng, S.; Wadsworth, S.; Campochiaro, P.; Heier, J.; Buggage, R. Preliminary results of a phase 1, open-label, safety and tolerability study of a single intravitreal injection of AAV2-sFLT01 in patients with neovascular age-related macular degeneration. Mol. Ther. 2016, 24, S98,  DOI: 10.1016/S1525-0016(16)33058-1
    65. 65
      Heier, J. S.; Kherani, S.; Desai, S.; Dugel, P.; Kaushal, S.; Cheng, S. H.; Delacono, C.; Purvis, A.; Richards, S.; Le-Halpere, A.; Connelly, J.; Wadsworth, S. C.; Varona, R.; Buggage, R.; Scaria, A.; Campochiaro, P. A. Intravitreous injection of AAV2- sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017, 390, 5061,  DOI: 10.1016/S0140-6736(17)30979-0
    66. 66
      Regenxbio Programs; REGENXBIO: Rockville, MD, 2020; http://ir.regenxbio.com/news-releases/news-release-details/regenxbio-reports-continued-progress-across-programs-year-end-0/ (accessed 2019-12-14).
    67. 67
      Campochiaro, P. A.; Lauer, A. K.; Sohn, E. H.; Mir, T. A.; Naylor, S.; Anderton, M. C.; Kelleher, M.; Harrop, R.; Ellis, S.; Mitrophanous, K. A. Lentiviral vector gene transfer of endostatin/ Angiostatin for macular degeneration (GEM) study. Hum. Gene Ther. 2017, 28, 99111,  DOI: 10.1089/hum.2016.117
    68. 68
      ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2020; https://clinicaltrials.gov/ (accessed 2020-01-10).
    69. 69
      Update on Clinical Trials for Macular Degeneration; BrightFocus Foundation: Clarksburg, MD, 2019; https://www.brightfocus.org/macular/article/update-clinical-trials-macular/ (accessed 2010-03-09).
    70. 70
      Graybug Vision Initiates Phase 1/2 Trial of GB-102 for Wet Age-related Macular Degeneration; Graybug Vision, Inc.: Redwood City, CA, 2017; https://graybug.com/graybug-vision-initiates-phase-12-trial-of-gb-102-for-wet-age-related-macular-degeneration/ (accessed 2019-02-21).
    71. 71
      An Oral Drug for Treatment of AMD?; Bryn Mawr Communications LLC: Wayne, PA, 2019; http://retinatoday.com/2016/08/an-oral-drug-for-treatment-of-amd/ (accessed 2019-02-21).
    72. 72
      X-82 to Treat Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02348359/ (accessed Jan 30, 2019).
    73. 73
      Joussen, A. M.; Wolf, S.; Kaiser, P. K.; Boyer, D.; Schmelter, T.; Sandbrink, R.; Zeitz, O.; Deeg, G.; Richter, A.; Zimmermann, T.; Hoechel, J.; Buetehorn, U.; Schmitt, W.; Stemper, B.; Boettger, M. K. The developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial. Br. J. Clin. Pharmacol. 2019, 85, 347355,  DOI: 10.1111/bcp.13794
    74. 74
      Abicipar; Molecular Partners, 2019; https://www.molecularpartners.com/our-products/abicipar/ (accessed 2019-01-13).
    75. 75
      OPT 302; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800043497 (accessed 2019-02-19).
    76. 76
      Jaffe, G. J.; Ciulla, T. A.; Ciardella, A. P.; Devin, F.; Dugel, P. U.; Eandi, C. M.; Masonson, H.; Monés, J.; Pearlman, J. A.; Quaranta-El Maftouhi, M.; Ricci, F.; Westby, K.; Patel, S. C. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 2017, 124, 224234,  DOI: 10.1016/j.ophtha.2016.10.010
    77. 77
      Rosenfeld, P. J.; Feuer, W. J. Lessons from recent phase III trial failures: don’t design phase III trials Based on retrospective subgroup analyses from phase II trials. Ophthalmology 2018, 125, 14881491,  DOI: 10.1016/j.ophtha.2018.06.002
    78. 78
      Ophthotech Announces Results from Third Phase 3 Trial of Fovista in Wet Age-Related Macular Degeneration; Ophthotech, 2018; https://investors.ivericbio.com/news-releases/news-release-details/ophthotech-announces-results-third-phase-3-trial-fovistar-wet/ (accessed 2018-05-26).
    79. 79
      Papadopoulos, K. P.; Kelley, R. K.; Tolcher, A. W.; Razak, A. R.; Van Loon, K.; Patnaik, A.; Bedard, P. L.; Alfaro, A. A.; Beeram, M.; Adriaens, L.; Brownstein, C. M.; Lowy, I.; Kostic, A.; Trail, P. A.; Gao, B.; DiCioccio, A. T.; Siu, L. L. A phase I first-in-human study of nesvacumab (REGN910), a fully human anti-angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 2016, 22, 13481355,  DOI: 10.1158/1078-0432.CCR-15-1221
    80. 80
      Regula, J. T.; Lundh Von Leithner, P.; Foxton, R.; Barathi, V. A.; Cheung, C. M.; Bo Tun, S. B.; Wey, Y. S.; Iwata, D.; Dostalek, M.; Moelleken, J.; Stubenrauch, K. G.; Nogoceke, E.; Widmer, G.; Strassburger, P.; Koss, M. J.; Klein, C.; Shima, D. T.; Hartmann, G. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 2016, 8, 12651288,  DOI: 10.15252/emmm.201505889
    81. 81
      Risitano, A. M.; Storek, M.; Sahelijo, L.; Doyle, M.; Dai, Y.; Weitz, I.; Marsh, J. C. W.; Elebute, M.; O’Connell, C. L.; Kulasekararaj, A. G.; Ramsingh, G.; Marotta, S.; Hellmann, A.; Lundberg, A. S. Safety and pharmacokinetics of the complement inhibitor TT30 in a phase I trial for untreated PNH patients. Blood 2015, 126, 2137,  DOI: 10.1182/blood.V126.23.2137.2137
    82. 82
      Kassa, E.; Ciulla, T. A.; Hussain, R. M.; Dugel, P. U. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin. Biol. Ther. 2019, 19, 335342,  DOI: 10.1080/14712598.2019.1575358
    83. 83
      Yehoshua, Z.; de Amorim Garcia Filho, C. A.; Nunes, R. P.; Gregori, G.; Penha, F. M.; Moshfeghi, A. A.; Zhang, K.; Sadda, S.; Feuer, W.; Rosenfeld, P. J. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the complete study. Ophthalmology 2014, 121, 693701,  DOI: 10.1016/j.ophtha.2013.09.044
    84. 84
      Cousins, S. W. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a phase 1 study. Invest. Ophthalmol. Vis. Sci. 2010, 51, e-Abstract 1251. 1251
    85. 85
      Lampalizumab—Genentech; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800024383 (accessed 2019-01-15).
    86. 86
      Tesidolumab—MorphoSys; Adis International Ltd, 2019; https://adisinsight.springer.com/drugs/800032650 (accessed Jan 17, 2019).
    87. 87
      Cheng, W. S.; Lu, D.; Chiang, C. H.; Chang, C. J. Overview of clinical trials for dry age-related macular degeneration. Yixue Yanjiu 2017, 37, 121129,  DOI: 10.4103/jmedsci.jmedsci_115_16
    88. 88
      Kubota, R.; Boman, N.; David, R.; Mallikaarjun, S.; Patil, S.; Birch, D. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator Article. Retina 2012, 32, 183188,  DOI: 10.1097/IAE.0b013e318217369e
    89. 89
      Holz, F. G.; Strauss, E. C.; Schmitz-Valckenberg, S.; van Lookeren Campagne, M. Geographic atrophy clinical features and potential therapeutic approaches. Ophthalmology 2014, 121, 10791091,  DOI: 10.1016/j.ophtha.2013.11.023
    90. 90
      Hanus, J.; Zhao, F.; Wang, S. Current therapeutic development for atrophic age-related macular degeneration. Br. J. Ophthalmol. 2016, 100, 122127,  DOI: 10.1136/bjophthalmol-2015-306972
    91. 91
      Motani, A.; Wang, Z.; Conn, M.; Siegler, K.; Zhang, Y.; Liu, Q.; Johnstone, S.; Xu, H.; Thibault, S.; Wang, Y.; Fan, P.; Connors, R.; Le, H.; Xu, G.; Walker, N.; Shan, B.; Coward, P. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J. Biol. Chem. 2009, 284, 76737680,  DOI: 10.1074/jbc.M809654200
    92. 92
      Zahn, G.; Vossmeyer, D.; Stragies, R.; Wills, M.; Wong, C. G.; Löffler, K. U.; Adamis, A. P.; Knolle, J. Preclinical evaluation of the novel small-molecule integrin inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch. Ophthalmol. 2009, 127, 13291335,  DOI: 10.1001/archophthalmol.2009.265
    93. 93
      Kuwada, S. K. Drug evaluation: volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr. Opin. Mol. Ther. 2007, 9, 9298
    94. 94
      Sonepcizumab—Lpath;Adis International Ltd. 2018; https://adisinsight.springer.com/drugs/800024045 (accessed 2018-12-29).
    95. 95
      Ibrahim, M. A.; Do, D. V.; Sepah, Y. J.; Shah, S. M.; Van Anden, E.; Hafiz, G.; Donahue, J. K.; Rivers, R.; Balkissoon, J.; Handa, J. T.; Campochiaro, P. A.; Nguyen, Q. D. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol. Toxicol. 2013, 14, 7,  DOI: 10.1186/2050-6511-14-7
    96. 96
      Taskintuna, I.; Abdalla Elsayed, M. E. A.; Schatz, P. Update on clinical trials in dry age related macular degeneration. Middle East Afr. J. Ophthalmol. 2016, 23, 1326,  DOI: 10.4103/0974-9233.173134
    97. 97
      Trimetazidine; DrugBank, 2019; https://www.drugbank.ca/drugs/DB09069/ (accessed May 12, 2019).
    98. 98
      Chiou, G. Is dry AMD treatable? a new ophthalmic solution may halt disease progression. Retina Today 2012, (May/June), 6971
    99. 99
      Jaffe, G. J.; Tao, W. A. A phase 2 study of encapsulated CNTF-secreting cell implant (NT-501) in patients with geographic atrophy associated with dry AMD-18-month. Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, May 2005, Fort Lauderdale, FL, 2005.
    100. 100
      Hernandez, M.; Urcola, J. H.; Vecino, E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp. Eye Res. 2008, 86, 798806,  DOI: 10.1016/j.exer.2008.02.008
    101. 101
      Clinical Study to Investigate Safety and Efficacy of GSK933776 in Adult Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration. ClinicalTrials.gov; National Institutes of Heath: Bethesda, MD, 2017; https://clinicaltrials.gov/ct2/show/NCT01342926.
    102. 102
      AKST4290: Targeting Eotaxin—Alkahest; Alkahest, 2020; https://www.alkahest.com/pipeline/akst4290/ (accessed 2020-01-10).
    103. 103
      (a) Quigley, H. A.; Broman, A. T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 2006, 90, 262267,  DOI: 10.1136/bjo.2005.081224 .
      (b) Heijl, A.; Leske, M. C.; Bengtsson, B.; Hyman, L.; Hussein, M. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 2002, 120, 12681279,  DOI: 10.1001/archopht.120.10.1268 .
      (c) What Is Glaucoma?; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/what-is-glaucoma/ (accessed 2019-03-15).
    104. 104
      Kwon, Y. H.; Fingert, J. H.; Kuehn, M. H.; Alward, W. L. Primary open-angle glaucoma. N. Engl. J. Med. 2009, 360, 11131124,  DOI: 10.1056/NEJMra0804630
    105. 105
      (a) Quigley, H. A. Glaucoma. Lancet 2011, 377, 13671377,  DOI: 10.1016/S0140-6736(10)61423-7 .
      (b) Greco, A.; Rizzo, M. I.; De Virgilio, A.; Gallo, A.; Fusconi, M.; de Vincentiis, M. Emerging concepts in glaucoma and review of the literature. Am. J. Med. 2016, 129, 1000.e7,  DOI: 10.1016/j.amjmed.2016.03.038
    106. 106
      Diagnosis and Treatment of Normal-Tension Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eyenet/article/diagnosis-treatment-of-normal-tension-glaucoma/ (accessed 2019-01-21).
    107. 107
      Secondary Glaucoma; Glaucoma Research Foundation, San Francisco, 2017; https://www.glaucoma.org/glaucoma/secondary-glaucoma.php/ (accessed 2019-03-12).
    108. 108
      Almasieh, M.; Wilson, A. M.; Morquette, B.; Cueva Vargas, J. L.; Di Polo, A. The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retinal Eye Res. 2012, 31, 152181,  DOI: 10.1016/j.preteyeres.2011.11.002
    109. 109
      Donegan, R. K.; Lieberman, R. L. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions: miniperspective. J. Med. Chem. 2016, 59, 788809,  DOI: 10.1021/acs.jmedchem.5b00828
    110. 110
      (a) Collaborative normal-tension glaucoma study group The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 1998, 126, 498505,  DOI: 10.1016/S0002-9394(98)00272-4 .
      (b) Jonas, J. B.; Aung, T.; Bourne, R. R.; Bron, A. M.; Ritch, R.; Panda-Jonas, S. Glaucoma. Lancet 2017, 390 (11), 21832193,  DOI: 10.1016/S0140-6736(17)31469-1
    111. 111
      (a) Glaucoma: Symptoms, Treatment and Prevention; All About Vision, 2019; https://www.allaboutvision.com/conditions/glaucoma.htm/ (accessed 2019-01-12).
      (b) Eyedrop Medicine for Glaucoma; American Academy of Ophthalmology, 2019; https://www.aao.org/eye-health/diseases/glaucoma-eyedrop-medicine/ (accessed 2019-01-19).
      (c) Babić, N. Fixed combinations of glaucoma medications. Srp. Arh. Celok. Lek. 2015, 143, 626631,  DOI: 10.2298/SARH1510626B
    112. 112
      (a) Melamed, S.; Ben Simon, G. J.; Levkovitch-Verbin, H. Selective trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch. Ophthalmol. 2003, 121, 957960,  DOI: 10.1001/archopht.121.7.957 .
      (b) Damji, K. F.; Shah, K. C.; Rock, W. J.; Bains, H. S.; Hodge, W. G. Selective laser trabeculoplasty vargon laser trabeculoplasty: a prospective randomised clinical trial. Br. J. Ophthalmol. 1999, 83, 718722,  DOI: 10.1136/bjo.83.6.718 .
      (c) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 5567,  DOI: 10.1097/00061198-200102000-00011 .
      (d) Ayala, M.; Chen, E. Comparison of selective laser trabeculoplasty (SLT) in primary open angle glaucoma and pseudoexfoliation glaucoma. Clin. Ophthalmol. 2011, 5, 14691673,  DOI: 10.2147/OPTH.S25636
    113. 113
      (a) Glaucoma Laser Trial Research Group The glaucoma laser trial (GLT) and glaucoma laser trial followup study: 7. Results. Am. J. Ophthalmol. 1995, 120, 718731,  DOI: 10.1016/S0002-9394(14)72725-4 .
      (b) Wong, M. O.; Lee, J. W.; Choy, B. N.; Chan, J. C.; Lai, J. S. Systematic review and meta-analysis on the efficacy of selective laser trabeculoplasty in open-angle glaucoma. Surv. Ophthalmol. 2015, 60, 3650,  DOI: 10.1016/j.survophthal.2014.06.006 .
      (c) McAlinden, C. Selective laser trabeculoplasty (SLT) vs other treatment modalities for glaucoma: systematic review. Eye 2014, 28, 249258,  DOI: 10.1038/eye.2013.267
    114. 114
      Gedde, S. J.; Schiffman, J. C.; Feuer, W. J.; Herndon, L. W.; Brandt, J. D.; Budenz, D. L. Treatment outcomes in the tube versus trabeculectomy (TVT) study after five years of follow-up. Am. J. Ophthalmol. 2012, 153, 789803,  DOI: 10.1016/j.ajo.2011.10.026
    115. 115
      (a) Edmunds, B.; Thompson, J.; Salmon, J.; Wormald, R. The national survey of trabeculectomy. III. early and late complications. Eye 2002, 16, 297303,  DOI: 10.1038/sj.eye.6700148 .
      (b) Spiegel, D.; Kobuch, K. Trabecular meshwork bypass tube shunt: initial case series. Br. J. Ophthalmol. 2002, 86, 12281231,  DOI: 10.1136/bjo.86.11.1228 .
      (c) Francis, B. A.; Singh, K.; Lin, S. C.; Hodapp, E.; Jampel, H. D.; Samples, J. R.; Smith, S. D. Novel glaucoma procedures: a report by the American academy of ophthalmology. Ophthalmology 2011, 118, 14661480,  DOI: 10.1016/j.ophtha.2011.03.028 .
      (d) Johnson, D. H.; Johnson, M. How does nonpenetrating glaucoma surgery work? aqueous outflow resistance and glaucoma surgery. J. Glaucoma 2001, 10, 5567,  DOI: 10.1097/00061198-200102000-00011
    116. 116
      (a) Prum, B. E., jr.; Herndon, L. W., jr.; Moroi, S. E.; Mansberger, S. L.; Stein, J. D.; Lim, M. C.; Rosenberg, L. F.; Gedde, S. J.; Williams, R. D. Primary angle closure preferred practice pattern guidelines. Ophthalmology 2016, 123, 140,  DOI: 10.1016/j.ophtha.2015.10.049 .
      (b) Lam, D. S. C.; Tham, C. C. Y.; Congdon, N. G.; Baig, N. Peripheral iridotomy for angle-closure glaucoma. Glaucoma 2015, 2, 708715,  DOI: 10.1016/B978-0-7020-5193-7.00072-8
    117. 117
      Glaucoma; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/glaucoma/diagnosis-treatment/drc-20372846/ (accessed 2019-02-21).
    118. 118
      Kwon, Y. H.; Kim, C. S.; Zimmerman, M. B.; Alward, W. L.; Hayreh, S. S. Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma. Am. J. Ophthalmol. 2001, 132, 4756,  DOI: 10.1016/S0002-9394(01)00912-6
    119. 119
      Chen, P. P. Blindness in patients with treated open-angle glaucoma. Ophthalmology 2003, 110, 726733,  DOI: 10.1016/S0161-6420(02)01974-7
    120. 120
      Lichter, P. R. Glaucoma clinical trials and what they mean for our patients. Am. J. Ophthalmol. 2003, 136, 136145,  DOI: 10.1016/S0002-9394(03)00143-0
    121. 121
      Weinreb, R. N.; Araie, M.; Susanna, R., Jr.; Goldberg, I.; Migdal, C.; Liebmann, J. M. Medical Treatment of Glaucoma; WGA Consensus Series; Kugler Publications: Amsterdam, 2010.
    122. 122
      Henson, D. B.; Shambhu, S. Relative risk of progressive glaucomatous visual field loss in patients enrolled and not enrolled in a prospective longitudinal study. Arch. Ophthalmol. 2006, 124, 14051408,  DOI: 10.1001/archopht.124.10.1405
    123. 123
      Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. ROCK-I and ROCK-II, two isoforms of rho-associated coil-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996, 392, 189193,  DOI: 10.1016/0014-5793(96)00811-3
    124. 124
      (a) Wang, J.; Liu, X.; Zhong, Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int. J. Oncol. 2013, 43, 13571367,  DOI: 10.3892/ijo.2013.2100 .
      (b) Wang, S. K.; Chang, R. T. An emerging treatment option for glaucoma: rho kinase inhibitors. Clin. Ophthalmol. 2014, 8, 883890,  DOI: 10.2147/OPTH.S41000 .
      (c) Chircop, M. Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells. Small GTPases 2014, 5, e29770,  DOI: 10.4161/sgtp.29770 .
      (d) Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446456,  DOI: 10.1038/nrm1128 .
      (e) Honjo, M.; Tanihara, H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn. J. Ophthalmol. 2018, 62, 109126,  DOI: 10.1007/s10384-018-0566-9 .
      (f) Ali, M. Recent advances in pharmacological therapy of glaucoma. Al-Shifa J. Ophthalmol. 2017, 13, 163165
    125. 125
      (a) Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressurelowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309315,  DOI: 10.1001/archophthalmol.2007.76 .
      (b) Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393395,  DOI: 10.1111/aos.12641
    126. 126
      Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: rsesults of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 3139,  DOI: 10.1016/j.jns.2005.06.003
    127. 127
      Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 22112215,  DOI: 10.1007/s40265-014-0333-2
    128. 128
      Ray, P.; Wright, J.; Adam, J.; Bennett, J.; Boucharens, S.; Black, D.; Cook, A.; Brown, R.; Epemolu, O.; Fletcher, D.; Haunso, A.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; Mestres, J.; de Man, J.; Morphy, R.; Rankovic, Z.; Sherborne, B.; Sherry, L.; van Straten, N.; Westwood, P.; Zaman, G. Z. R. Fragment-based discovery of 6- substituted isoquinolin-1-amine based ROCK-I inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 97101,  DOI: 10.1016/j.bmcl.2010.11.060
    129. 129
      Pan, P.; Shen, M.; Yu, H.; Li, Y.; Li, D.; Hou, T. Advances in the development of Rho-associated protein kinase (ROCK) inhibitors. Drug Discovery Today 2013, 18, 13231333,  DOI: 10.1016/j.drudis.2013.09.010
    130. 130
      Henderson, A. J.; Hadden, M.; Guo, C.; Douglas, N.; Decornez, H.; Hellberg, M. R.; Rusinko, A.; McLaughlin, M.; Sharif, N.; Drace, C.; Patil, R. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 11371140,  DOI: 10.1016/j.bmcl.2009.12.012
    131. 131
      Chen, H.-H.; Namil, A.; Severns, B.; Ward, J.; Kelly, C.; Drace, C.; McLaughlin, M. A.; Yacoub, S.; Li, B.; Patil, R.; Sharif, N.; Hellberg, M. R.; Rusinko, A.; Pang, I.-H.; Combrink, K. D. In vivo optimization of 2,3-diaminopyrazine Rho kinase inhibitors for the treatment of glaucoma. Bioorg. Med. Chem. Lett. 2014, 24, 18751879,  DOI: 10.1016/j.bmcl.2014.03.017
    132. 132
      Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M. D.; Lin, L.; Ruiz, C.; Schurer, S. C.; Inoue, T.; Rao, P. V.; Schroter, T.; LoGrasso, P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 2008, 51, 66426645,  DOI: 10.1021/jm800986w
    133. 133
      Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2- (Aminomethyl)-5-[(pyridin-4-yl) carbamoyl] phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 64426446,  DOI: 10.1016/j.bmcl.2013.09.040
    134. 134
      deLong, M. A.; Yingling, J.; Lin, C. W.; Sherman, B.; Sturdivant, J.; Heintzelman, G.; Lathem, C.; van Haarlem, T.; Kopczynski, C. Discovery and SAR of a class of ocularly-active compounds displaying a dual mechanism of activity for the treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 3867
    135. 135
      Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 17411756,  DOI: 10.1016/j.ophtha.2018.04.040
    136. 136
      Schehlein, E. M.; Robin, A. L. Rho-associated kinase inhibitors: evolving strategies in glaucoma treatment. Drugs 2019, 79, 10311036,  DOI: 10.1007/s40265-019-01130-z
    137. 137
      Kopczynski, C.; Lin, C. W.; deLong, M.; Yingling, J.; Heintzelman, G.; Sturdivant, J.; Sherman, B.; Laethem, C.; van Haarlem, T. IOP-lowering efficacy and tolerability of AR-13324, a dual mechanism kinase inhibitor for treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 2012, 53, 5080
    138. 138
      Wang, R. F.; Williamson, J. E.; Kopczynski, C.; Serle, J. B. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J. Glaucoma 2015, 24, 5154,  DOI: 10.1097/IJG.0b013e3182952213
    139. 139
      Li, G.; Mukherjee, D.; Navarro, I.; Ashpole, N. E.; Sherwood, J. M.; Chang, J.; Overby, D. R.; Yuan, F.; Gonzalez, P.; Kopczynski, C. C.; Farsiu, S.; Stamer, W. D. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur. J. Pharmacol. 2016, 787, 2031,  DOI: 10.1016/j.ejphar.2016.04.002
    140. 140
      Lin, C. W.; Sherman, B.; Moore, L. A.; Laethem, C. L.; Lu, D. W.; Pattabiraman, P. P.; Rao, P. V.; deLong, M. A.; Kopczynski, C. C. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J. Ocul. Pharmacol. Ther. 2018, 34, 4051,  DOI: 10.1089/jop.2017.0023
    141. 141
      Ren, R.; Li, G.; Le, T. D.; Kopczynski, C.; Stamer, W. D.; Gong, H. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest. Ophthalmol. Visual Sci. 2016, 57, 61976209,  DOI: 10.1167/iovs.16-20189
    142. 142
      Bacharach, J.; Dubiner, H. B.; Levy, B.; Kopczynski, C. C.; Novack, G. D. Double-masked, randomized, dose response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology 2015, 122, 302307,  DOI: 10.1016/j.ophtha.2014.08.022
    143. 143
      (a) Serle, J. B.; Katz, L. J.; McLaurin, E.; Heah, T.; Ramirez-Davis, N.; Usner, D. W.; Novack, G. D.; Kopczynski, C. C. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am. J. Ophthalmol. 2018, 186, 116127,  DOI: 10.1016/j.ajo.2017.11.019 .
      (b) Levy, B.; Ramirez, N.; Novack, G. D.; Kopczynski, C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am. J. Ophthalmol. 2015, 159, 980985,  DOI: 10.1016/j.ajo.2015.01.026
    144. 144
      (a) Aerie Pharmaceuticals Reports Positive RoclatanTM (Netarsudil/Latanoprost Ophthalmic Solution) 0.02%/0.005% Phase 3 Topline Efficacy Results; Business Wire, 2019; https://www.businesswire.com/news/home/20170524006043/en/Aerie-Pharmaceuticals-Reports-Positive-Roclatan%E2%84%A2-netarsudillatanoprost-ophthalmic/ (accessed Aug 18, 2019).
      (b) Bacharach, J.; Khouri, A. S.; Kopczynski, C. C.; Heah, T.; Lewis, R. A double-masked, randomized, multi-center, active controlled, parallel group, 6-month study assessing the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution, 0.02% QD compared to timolol maleate ophthalmic solution, 0.5% bid. Am. Acad. Optom. Abst. 2017, E351
    145. 145
      Lewis, R.; Levy, B.; Ramirez, N.; Kopczynski, C. C.; Usner, D. W.; Novack, G. D. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br. J. Ophthalmol. 2016, 100, 339344,  DOI: 10.1136/bjophthalmol-2015-306778
    146. 146
      RoclatanTM Mercury 2 Phase 3 Topline Results; Aerie Pharmaceuticals Inc, 2016; http://investors.aeriepharma.com/static-files/fb9a0c3f-7255-4b50-97b2-450a2ba5d139/ (accessed Sep 14, 2019).
    147. 147
      (a) Tokushige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uehata, M.; Tanihara, H. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest. Ophthalmol. Visual Sci. 2007, 48, 32163222,  DOI: 10.1167/iovs.05-1617 .
      (b) Whitlock, N. A.; Harrison, B.; Mixon, T.; Yu, X.-Q.; Wilson, A.; Gerhardt, B.; Eberhart, D. E.; Abuin, A.; Rice, D. S. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J. Ocul. Pharmacol. Ther. 2009, 25, 187194,  DOI: 10.1089/jop.2008.0142
    148. 148
      Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure–lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch. Ophthalmol. 2008, 126, 309315,  DOI: 10.1001/archophthalmol.2007.76
    149. 149
      Inoue, T.; Tanihara, H.; Tokushige, H.; Araie, M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol. 2015, 93, e393e395,  DOI: 10.1111/aos.12641
    150. 150
      Kopczynski, C.; Novack, G. D.; Swearingen, D.; van Haarlem, T. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br. J. Ophthalmol. 2013, 97, 567572,  DOI: 10.1136/bjophthalmol-2012-302466
    151. 151
      Williams, R. D.; Novack, G. D.; van Haarlem, T.; Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 2011, 152, 834841,  DOI: 10.1016/j.ajo.2011.04.012
    152. 152
      Tanna, A. P.; Johnson, M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology 2018, 125, 17411756,  DOI: 10.1016/j.ophtha.2018.04.040
    153. 153
      Garnock-Jones, K. P. Ripasudil: first global approval. Drugs 2014, 74, 22112215,  DOI: 10.1007/s40265-014-0333-2
    154. 154
      (a) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013, 131, 12881295,  DOI: 10.1001/jamaophthalmol.2013.323 .
      (b) Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115) over 24 h in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol. 2015, 93, e254e260,  DOI: 10.1111/aos.12599
    155. 155
      Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Araie, M. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am. J. Ophthalmol. 2013, 156, 731736,  DOI: 10.1016/j.ajo.2013.05.016
    156. 156
      Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Suganami, H.; Araie, M. Additive intraocular pressure–lowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 2015, 133, 755761,  DOI: 10.1001/jamaophthalmol.2015.0525
    157. 157
      Tanihara, H.; Inoue, T.; Yamamoto, T.; Kuwayama, Y.; Abe, H.; Fukushima, A.; Suganami, H.; Araie, M. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016, 94, e26e34,  DOI: 10.1111/aos.12829
    158. 158
      Terao, E.; Nakakura, S.; Fujisawa, Y.; Fujio, Y.; Matsuya, K.; Kobayashi, Y.; Tabuchi, H.; Yoneda, T.; Fukushima, A.; Kiuchi, Y. Time course of conjunctival hyperemia induced by a Rho-kinase inhibitor anti-glaucoma eye drop: ripasudil 0.4%. Curr. Eye Res. 2017, 42, 738742,  DOI: 10.1080/02713683.2016.1250276
    159. 159
      Inoue, K.; Okayama, R.; Shiokawa, M.; Ishida, K.; Tomita, G. Efficacy and safety of adding ripasudil to existing treatment regimens for reducing intraocular pressure. Int. Ophthalmol. 2017, 38, 9398,  DOI: 10.1007/s10792-016-0427-9
    160. 160
      (a) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. Efficacy of the additional use of ripasudil, a Rho-kinase inhibitor, in patients with glaucoma inadequately controlled under maximum medical therapy. J. Glaucoma 2017, 26, 96100,  DOI: 10.1097/IJG.0000000000000552 .
      (b) Inazaki, H.; Kobayashi, S.; Anzai, Y.; Satoh, H.; Sato, S.; Inoue, M.; Yamane, S.; Kadonosono, K. One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. Graefe's Arch. Clin. Exp. Ophthalmol. 2017, 255, 20092015,  DOI: 10.1007/s00417-017-3727-5
    161. 161
      Sato, S.; Hirooka, K.; Nitta, E.; Ukegawa, K.; Tsujikawa, A. Additive intraocular pressure lowering effects of the Rho kinase inhibitor, ripasudil in glaucoma patients not able to obtain adequate control after other maximal tolerated medical therapy. Adv. Ther. 2016, 33, 16281634,  DOI: 10.1007/s12325-016-0389-3
    162. 162
      Yamada, H.; Yoneda, M.; Inaguma, S.; Gosho, M.; Murasawa, Y.; Isogai, Z.; Zako, M. A Rho-associated kinase inhibitor protects permeability in a cell culture model of ocular disease, and reduces aqueous flare in anterior uveitis. J. Ocul. Pharmacol. Ther. 2017, 33, 176185,  DOI: 10.1089/jop.2016.0085
    163. 163
      Yasuda, M.; Takayama, K.; Kanda, T.; Taguchi, M.; Someya, H.; Takeuchi, M. Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension. PLoS One 2017, 12, e0185305,  DOI: 10.1371/journal.pone.0185305
    164. 164
      Yamamoto, K.; Maruyama, K.; Himori, N.; Omodaka, K.; Yokoyama, Y.; Shiga, Y.; Morin, R.; Nakazawa, T. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 71267136,  DOI: 10.1167/iovs.13-13842
    165. 165
      (a) Zhong, Y.; Yang, Z.; Huang, W. C.; Luo, X. Adenosine, adenosine receptors and glaucoma: An updated overview. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 28822890,  DOI: 10.1016/j.bbagen.2013.01.005 .
      (b) Shim, M. S.; Kim, K. Y.; Ju, W. K. Role of cyclic AMP in the eye with glaucoma. BMB Rep 2017, 50, 6070,  DOI: 10.5483/BMBRep.2017.50.2.200
    166. 166
      (a) Chen, J.; Runyan, S. A.; Robinson, M. R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol. 2011, 5, 667677,  DOI: 10.2147/OPTH.S15971 .
      INO-8875; Inotek Pharmaceuticals, 2019; http://www.inotekcorp.com/content/ino-8875.asp (accessed 2019-01-19).
    167. 167
      (a) Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Klotz, K. N.; Linden, J. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527552.
      (b) Jacobson, K. A.; Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discovery 2006, 5, 247264,  DOI: 10.1038/nrd1983
    168. 168
      Webb, R. L.; Sills, M. A.; Chovan, J. P.; Peppard, J. V.; Francis, J. E. Development of tolerance to the antihypertensive effects of highly selective adenosine A2a agonists, upon chronic administration. J. Pharmacol. Exp. Ther. 1993, 267, 287295
    169. 169
      Phase 1/2 Clinical Trial for OPA-6566, 2019; https://adisinsight.springer.com/drugs/800032852 (accessed 2019-01-21).
    170. 170
      Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125132,  DOI: 10.1089/jop.2009.0120
    171. 171
      (a) Kerwin, J. F.; Heller, M. The arginine-nitric oxide pathway a target for new drugs. Med. Res. Rev. 1994, 14, 2374,  DOI: 10.1002/med.2610140103 .
      (b) Wink, D. A.; Mitchell, J. R. Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanism of nitric oxide. Free Radical Biol. Med. 1998, 25, 434456,  DOI: 10.1016/S0891-5849(98)00092-6
    172. 172
      (a) Cavet, M. E.; Vittitow, J. L.; Impagnatiello, F.; Ongini, E.; Bastia, E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest. Ophthalmol. Visual Sci. 2014, 55, 50055015,  DOI: 10.1167/iovs.14-14515 .
      (b) Chiou, G. C. Effects of nitric oxide on eye diseases and their treatment. J. Ocul. Pharmacol. Ther. 2001, 17, 189198,  DOI: 10.1089/10807680151125555 .
      (c) Haefliger, I. O.; Meyer, P.; Flammer, J.; Lüscher, T. F. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology. Surv. Ophthalmol. 1994, 39, 123132,  DOI: 10.1016/0039-6257(94)90157-0
    173. 173
      Aliancy, J.; Stamer, W. D.; Wirostko, B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol. Ther. 2017, 6, 221232,  DOI: 10.1007/s40123-017-0094-6
    174. 174
      (a) Costa, V. P.; Harris, A.; Anderson, D.; Stodtmeister, R.; Cremasco, F.; Kergoat, H.; Lovasik, J.; Stalmans, I.; Zeitz, O.; Lanzl, I.; Gugleta, K.; Schmetterer, L. Ocular perfusion pressure in glaucoma. Acta Ophthalmol. 2014, 92, e252e266,  DOI: 10.1111/aos.12298 .
      (b) Resch, H.; Garhofer, G.; Fuchsjäger-Mayrl, G.; Hommer, A.; Schmetterer, L. Endothelial dysfunction in glaucoma. Acta Ophthalmol. 2009, 87, 412,  DOI: 10.1111/j.1755-3768.2007.01167.x
    175. 175
      Nitric Oxide (NO)-Donors: The Nicox Expertise; Nicox, 2019; http://www.nicox.com/rd/ (accessed 2019-08-21).
    176. 176
      Product and Product Candidates; Nicox, 2020 https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
    177. 177
      (a) Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V. L.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250255,  DOI: 10.1016/j.exer.2011.03.001 .
      Vyzulta for Patients with Glaucoma; Bausch & Lomb Incorporated, 2018; https://www.vyzulta.com/ (accessed 2019-08).
    178. 178
      Cavet, M. E.; Vollmer, T. R.; Harrington, K. L.; VanDerMeid, K.; Richardson, M. E. Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Invest. Ophthalmol. Visual Sci. 2015, 56, 41084116,  DOI: 10.1167/iovs.14-16015
    179. 179
      Garcia, G. A.; Ngai, P.; Mosaed, S.; Lin, K. Y. Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin. Ophthalmol. 2016, 10, 20352050,  DOI: 10.2147/OPTH.S103985
    180. 180
      Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 65586564,  DOI: 10.1167/iovs.15-17190
    181. 181
      Krauss, A. H.; Impagnatiello, F.; Toris, C. B.; Gale, D. C.; Prasanna, G.; Borghi, V.; Chiroli, V.; Chong, W. K.; Carreiro, S. T.; Ongini, E. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2a agonist, in preclinical models. Exp. Eye Res. 2011, 93, 250255,  DOI: 10.1016/j.exer.2011.03.001
    182. 182
      Araie, M.; Sforzolini, B. S.; Vittitow, J.; Weinreb, R. N. Evaluation of the effect of latanoprostene bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24 h in Healthy Japanese Subjects. Adv. Ther. 2015, 32, 11281139,  DOI: 10.1007/s12325-015-0260-y
    183. 183
      Weinreb, R. N.; Ong, T.; Scassellati Sforzolini, B.; Vittitow, J. L.; Singh, K.; Kaufman, P. L. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the voyager study. Br. J. Ophthalmol. 2015, 99, 738745,  DOI: 10.1136/bjophthalmol-2014-305908
    184. 184
      Liu, J. H. K.; Slight, J. R.; Vittitow, J. L.; Scassellati Sforzolini, B.; Weinreb, R. N. Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 h. Am. J. Ophthalmol. 2016, 169, 249257,  DOI: 10.1016/j.ajo.2016.04.019
    185. 185
      Weinreb, R. N.; Scassellati Sforzolini, B.; Vittitow, J.; Liebmann, J. Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the apollo study. Ophthalmology 2016, 123, 965973,  DOI: 10.1016/j.ophtha.2016.01.019
    186. 186
      Medeiros, F. A.; Martin, K. R.; Peace, J.; Scassellati Sforzolini, B.; Vittitow, J. L.; Weinreb, R. N. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular Hypertension: the LUNAR Study. Am. J. Ophthalmol. 2016, 168, 250259,  DOI: 10.1016/j.ajo.2016.05.012
    187. 187
      Kawase, K.; Vittitow, J. L.; Weinreb, R. N.; Araie, M. Long-term safety and efficacy of latanoprostene bunod 0.024% in japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER Study. Adv. Ther. 2016, 33, 16121627,  DOI: 10.1007/s12325-016-0385-7
    188. 188
      Borghi, V.; Bastia, E.; Guzzetta, M.; Chiroli, V.; Toris, C. B.; Batugo, M. R.; Carreiro, S. T.; Chong, W. K.; Gale, D. C.; Kucera, D. J.; Jia, L.; Prasanna, G.; Ongini, E.; Krauss, A. H.; Impagnatiello, F. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J. Ocul. Pharmacol. Ther. 2010, 26, 125132,  DOI: 10.1089/jop.2009.0120
    189. 189
      Impagnatiello, F.; Borghi, V.; Gale, D.; Batugo, M.; Guzzetta, M.; Brambilla, S.; Carreiro, S.; Chong, W.; Prasanna, G.; Chiroli, V.; Ongini, E.; Krauss, A. H. A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs. Exp. Eye Res. 2011, 93, 243249,  DOI: 10.1016/j.exer.2011.02.006
    190. 190
      Pipeline of Ophthalmic Therapeutics; Nicox, 2020; https://www.nicox.com/rd/#!/candidates/ (accessed 2020-01-21).
    191. 191
      Impagnatiello, F.; Toris, C. B.; Batugo, M.; Prasanna, G.; Borghi, V.; Bastia, E.; Ongini, E.; Krauss, A. H. Intraocular pressure–lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models. Invest. Ophthalmol. Visual Sci. 2015, 56, 65586564,  DOI: 10.1167/iovs.15-17190
    192. 192
      (a) News; Nicox, 2020; https://www.nicox.com/news-media/news/#2019/ (accessed 2020-01-10).
      (b) Nicox Presents First Data on Promising New Class of Nitric Oxide (NO)-Donating Compounds for Glaucoma at the ARVO 2019 Annual Meeting; Nicox, 2019; https://www.nicox.com/news-media/presents-first-data-on-promising-new-class-of-nitric-oxide-no-donating-compounds-for-glaucoma-at-the-arvo-2019-annual-meeting/ (accessed 2020-01-10).
    193. 193
      (a) Nicox Announces the Presentation of NCX 667 Scientific Data at AOPT 2017; Nicox, 2017; https://www.marketscreener.com/NICOX-25281955/news/Nicox-announces-the-presentation-of-NCX-667-scientific-data-at-AOPT-2017-23911286/ (accessed 2020-01-10).
      (b) NCX 667, A Novel Nitric Oxide (NO) Donor, Effectively Reduces Intraocular Pressure (IOP) in Three Models of Ocular Hypertension and Glaucoma, 2020; https://congresso.sifweb.org/archivio/cong37/abs/650.pdf/ (accessed 2020-01-10).
    194. 194
      NCX 1741, A Novel NO-donating Derivative of the Phosphodiesterase-5 Inhibitor Avanafil, Reduces IOP in Models of Ocular Hypertension and Glaucoma; Nicox, 2020; https://iovs.arvojournals.org/article.aspx?articleid=2743508 (accessed 2020-01-10).
    195. 195
      Arber, S.; Barbayannis, F. A.; Hanser, H.; Schneider, C.; Stanyon, C. A.; Bernard, O.; Caroni, P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 1998, 393, 805809,  DOI: 10.1038/31729
    196. 196
      Harrison, B. A.; Whitlock, N. A.; Voronkov, M. V.; Almstead, Z. Y.; Gu, K. J.; Mabon, R.; Gardyan, M.; Hamman, B. D.; Allen, J.; Gopinathan, S.; McKnight, B.; Crist, M.; Zhang, Y.; Liu, Y.; Courtney, L. F.; Key, B.; Zhou, J.; Patel, N.; Yates, P. W.; Liu, Q.; Wilson, A. G.; Kimball, S. D.; Crosson, C. E.; Rice, D. S.; Rawlins, D. B. Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma. J. Med. Chem. 2009, 52, 65156518,  DOI: 10.1021/jm901226j
    197. 197
      Harrison, B. A.; Almstead, Z. Y.; Burgoon, H.; Gardyan, M.; Goodwin, N. C.; Healy, J.; Liu, Y.; Mabon, R.; Marinelli, B.; Samala, L.; Zhang, Y.; Stouch, T. R.; Whitlock, N. A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A. G.; Hamman, B. D.; Rice, D. S.; Rawlins, D. B. Discovery and development of LX7101, a dual LIM-Kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med. Chem. Lett. 2015, 6, 8488,  DOI: 10.1021/ml500367g
    198. 198
      (a) Ganesh, T. Prostanoid receptor EP2 as a therapeutic target. J. Med. Chem. 2014, 57, 44544465,  DOI: 10.1021/jm401431x .
      (b) Sugimoto, Y.; Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 2007, 282, 1161311617,  DOI: 10.1074/jbc.R600038200 .
      (c) Krauss, A. H.; Chen, J.; Kharlamb, A.; Burk, R. M.; Holoboski, M.; Posner, M.; Gil, D. W.; Burke, J. A.; Woodward, D. F. A selective prostanoid EP2 receptor agonist (Butaprost) normalizes glaucomatous monkey intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2002, 43, 41074108
    199. 199
      Iwamura, R.; Tanaka, M.; Okanari, E.; Kirihara, T.; Odani-Kawabata, N.; Shams, N.; Yoneda, K. Identification of a selective, non-prostanoid EP2 receptor agonist for the treatment of glaucoma: omidenepag and its prodrug omidenepag isopropyl. J. Med. Chem. 2018, 61, 68696891,  DOI: 10.1021/acs.jmedchem.8b00808
    200. 200
      Diabetic Retinopathy; Diabetes.co.uk, 2019; https://www.diabetes.co.uk/diabetes-complications/diabetic-retinopathy.html/ (accessed 2019-01-31).
      (b) Standards of Medical Care in Diabetes–2015, Summary of Revisions. Diabetes Care 2015, 38, S4. DOI: 10.2337/dc15-S003
    201. 201
      Duh, E. J.; Sun, J. K.; Stitt, A. W. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017, 2, e93751,  DOI: 10.1172/jci.insight.93751
    202. 202
      Stitt, A. W.; Curtis, T. M.; Chen, M.; Medina, R. J.; McKay, G. J.; Jenkins, A.; Gardiner, T. A.; Lyons, T. J.; Hammes, H. P.; Simó, R.; Lois, N. The progress in understanding and treatment of diabetic retinopathy. Prog. Retinal Eye Res. 2016, 51, 156186,  DOI: 10.1016/j.preteyeres.2015.08.001
    203. 203
      (a) Frey, T.; Antonetti, D. A. Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid. Redox Signaling 2011, 15, 12711284,  DOI: 10.1089/ars.2011.3906 .
      (b) Zhang, X.; Zeng, H.; Bao, S.; Wang, N.; Gillies, M. C. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014, 4, 27,  DOI: 10.1186/2045-3701-4-27
    204. 204
      (a) Romero-Aroca, P.; Baget-Bernaldiz, M.; Pareja-Rios, A.; Lopez-Galvez, M.; Navarro-Gil, R.; Verges, R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J. Diabetes Res. 2016, 2016, 2156273,  DOI: 10.1155/2016/2156273 .
      Diabetic Retinopathy; Mayo Clinic: Rochester, MN, 2018; https://www.mayoclinic.org/diseases-conditions/diabetic-retinopathy/symptoms-causes/syc-20371611// (accessed 2019-02-21).
    205. 205
      (a) Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54, 16151625,  DOI: 10.2337/diabetes.54.6.1615 .
      (b) Tarr, J. M.; Kaul, K.; Chopra, M.; Kohner, E. M.; Chibber, R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. 2013, 2013, 343560,  DOI: 10.1155/2013/343560
    206. 206
      Yuuki, T.; Kanda, T.; Kimura, Y.; Kotajima, N.; Tamura, J.; Kobayashi, I.; Kishi, S. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J. Diab. Complic. 2001, 15, 257259,  DOI: 10.1016/S1056-8727(01)00155-6
    207. 207
      (a) Tien, T.; Zhang, J.; Muto, T.; Kim, D.; Sarthy, V. P.; Roy, S. High glucose induces mitochondrial dysfunction in retinal muller cells: Implications for diabetic retinopathy. Invest. Ophthalmol. Visual Sci. 2017, 58, 29152921,  DOI: 10.1167/iovs.16-21355 .
      (b) Sasaki, M.; Ozawa, Y.; Kurihara, T.; Kubota, S.; Yuki, K.; Noda, K.; Kobayashi, S.; Ishida, S.; Tsubota, K. Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. Diabetologia 2010, 53, 971979,  DOI: 10.1007/s00125-009-1655-6
    208. 208
      (a) Mitchell, P.; Bandello, F.; Schmidt-Erfurth, U.; Lang, G. E.; Massin, P.; Schlingemann, R. O.; Sutter, F.; Simader, C.; Burian, G.; Gerstner, O.; Weichselberger, A. the restore study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011, 118, 615625,  DOI: 10.1016/j.ophtha.2011.01.031 .
      (b) Sultan, M. B.; Zhou, D.; Loftus, J.; Dombi, T.; Ice, K. S. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011, 118, 11071118,  DOI: 10.1016/j.ophtha.2011.02.045 .
      (c) Heier, J. S.; Korobelnik, J. F.; Brown, D. M.; Schmidt-Erfurth, U.; Do, D. V.; Midena, E.; Boyer, D. S.; Terasaki, H.; Kaiser, P. K.; Marcus, D. M.; Nguyen, Q. D.; Jaffe, G. J.; Slakter, J. S.; Simader, C.; Soo, Y.; Schmelter, T.; Vitti, R.; Berliner, A. J.; Zeitz, O.; Metzig, C.; Holz, F. G. Intravitreal aflibercept for diabetic macular edema: 148-week results from the vista and vivid studies. Ophthalmology 2016, 123, 23762385,  DOI: 10.1016/j.ophtha.2016.07.032 .
      (d) The Diabetic Retinopathy Clinical Research Network Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N. Engl. J. Med. 2015, 372, 11931203,  DOI: 10.1056/NEJMoa1414264
    209. 209
      (a) Elman, M. J.; Aiello, L. P.; Beck, R. W.; Bressler, N. M.; Bressler, S. B.; Edwards, A. R.; Ferris, F. L.; Friedman, S. M.; Glassman, A. R.; Miller, K. M.; Scott, I. U.; Stockdale, C. R.; Sun, J. K. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010, 117, 10641077,  DOI: 10.1016/j.ophtha.2010.02.031 .
      (b) Pacella, F.; Romano, M. R.; Turchetti, P.; Tarquini, G.; Carnovale, A.; Mollicone, A.; Mastromatteo, A.; Pacella, E. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int. J. Ophthalmol. 2016, 9, 14271432,  DOI: 10.18240/ijo.2016.10.10
    210. 210
      (a) Wroblewski, J. J.; Hu, A. Y. Topical squalamine 0.2% and intravitreal ranibizumab 0.5 mg as combination therapy for macular edema due to branch and central retinal vein occlusion: An open-label, randomized study. Ophthalmic Surg. Lasers Imag. Retina 2016, 47, 914923,  DOI: 10.3928/23258160-20161004-04 .
      (b) Campochiaro, P. A.; Khanani, A.; Singer, M.; Patel, S.; Boyer, D.; Dugel, P.; Kherani, S.; Withers, B.; Gambino, L.; Peters, K.; Brigell, M. Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology 2016, 123, 17221730,  DOI: 10.1016/j.ophtha.2016.04.025 .
      (c) Anti-vasculaR Endothelial Growth Factor plUs Anti-angiopoietin 2 in Fixed comBination therapY: Evaluation for the Treatment of Diabetic Macular Edema (RUBY). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02712008/ (accessed 2020-01-05).
      (d) A Study of Faricimab (RO6867461) in Participants With Center-involving Diabetic Macular Edema (BOULEVARD). ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2019; https://clinicaltrials.gov/ct2/show/NCT02699450/ (accesed Jan 5, 2020).
    211. 211
      (a) Safety Study of Intravitreal EBI-031 Given as a Single or Repeat Injection to Subjects with Diabetic Macular Edema; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2016; https://clinicaltrials.gov/ct2/show/NCT02842541/ (accesssed Jan 20, 2019).
      (b) Ranibizumab for Edema of the Macula in Diabetes: Protocol 4 with Tocilizumab: the read-4 Study; ClinicalTrials.gov; National Insitutes of Health: Bethesda, MD, 2018; https://clinicaltrials.gov/ct2/show/NCT02511067/ (accessed 2019-01-20).
    212. 212
      (a) Early Treatment Diabetic Retinopathy Study Research Group Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. early treatment diabetic retinopathy study report number 2. Ophthalmology 1987, 94, 761774,  DOI: 10.1016/S0161-6420(87)33527-4 .
      (b) Patz, A.; Fine, S.; Finkelstein, D.; Prout, T.; Aiello, L.; Bradley, R.; Briones, J. C.; Myers, F.; Bresnick, G.; de Venecia, G.; Stevens, T. S.; Wallow, I. H.L.; Chandra, S. R.; Norton, E.; Blankenship, G.; Harris, J.; Knobloch, W.; Goetz, F.; Ramsay, R. C.; McMeel, J. W.; Martin, D.; Goldberg, M.; Huamonte, F.; Peyman, G.; Straatsma, B.; Kopelow, S.; van Heuven, W.A.J.; Kassoff, A.; Feman, S.; Watzke, R.; Mensher, J.; Tasman, W.; Annesley, W.; Leonard, B.; Canny, C.; Joffe, L.; Pheasant, T.; Riekhof, F. T.; Dahl, M.; Bohart, W.; Clarke, D.; Berrocal, J.; Ramos-Umpierre, A.; Velazquez, G.; Margherio, R.; Nachazel, D.; McLean, E.; Guzak, S.; Knatterud, G.; Klimt, C.; Hillis, A.; Makuc, D.; Davis, M.; MacCormick, A.; Magli, Y.; Segal, P. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology 1978, 85, 82106,  DOI: 10.1016/S0161-6420(78)35693-1
    213. 213
      (a) Blumenkranz, M. S.; Yellachich, D.; Andersen, D. E.; Wiltberger, M. W.; Mordaunt, D.; Marcellino, G. R.; Palanker, D. Semiautomated patterned scanning laser for retinal photocoagulation. Retina 2006, 26, 370376,  DOI: 10.1097/00006982-200603000-00024 .
      (b) Vujosevic, S.; Martini, F.; Convento, E.; Longhin, E.; Kotsafti, E.; Parrozzani, R.; Midena, E. Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. Curr. Med. Chem. 2013, 20, 32673271,  DOI: 10.2174/09298673113209990030 .
      (c) Neubauer, A. S.; Langer, J.; Liegl, R.; Haritoglou, C.; Wolf, A.; Kozak, I.; Seidensticker, F.; Ulbig, M.; Freeman, W. R.; Kampik, A.; Kernt, M. Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin. Ophthalmol. 2013, 7, 121128,  DOI: 10.2147/OPTH.S38559
    214. 214
      (a) Paradies, G.; Petrosillo, G.; Paradies, V.; Ruggiero, F. M. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 2009, 45, 643650,  DOI: 10.1016/j.ceca.2009.03.012 .
      (b) Alam, N. M.; Mills, W. C. T.; Wong, A. A.; Douglas, R. M.; Szeto, H. H.; Prusky, G. T. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis. Models & Mech. 2015, 8, 701710,  DOI: 10.1242/dmm.020248 .
      (c) Gebka, A.; Serkies-Minuth, E.; Raczynska, D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflammation 2014, 2014, 131538,  DOI: 10.1155/2014/131538
    215. 215
      (a) Li, S. Y.; Fu, Z. J.; Ma, H.; Jang, W. C.; So, K. F.; Wong, D.; Lo, A. C. Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusion. Invest. Ophthalmol. Visual Sci. 2009, 50, 836843,  DOI: 10.1167/iovs.08-2310 .
      (b) Li, S. Y.; Fung, F. K.; Fu, Z. J.; Wong, D.; Chan, H. H.; Lo, A. C. Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: In vivo and in vitro studies. Invest. Ophthalmol. Visual Sci. 2012, 53, 59765984,  DOI: 10.1167/iovs.12-10007 .
      (c) McVicar, C. M.; Hamilton, R.; Colhoun, L. M.; Gardiner, T. A.; Brines, M.; Cerami, A.; Stitt, A. W. Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes 2011, 60, 29953005,  DOI: 10.2337/db11-0026 .
      (d) Canning, P.; Kenny, B. A.; Prise, V.; Glenn, J.; Sarker, M. H.; Hudson, N.; Brandt, M.; Lopez, F. J.; Gale, D.; Luthert, P. J.; Adamson, P.; Turowski, P.; Stitt, A. W. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 72137218,  DOI: 10.1073/pnas.1514213113
    216. 216
      KalVista for DME; KalVista Pharmaceuticals, 2020; https://www.kalvista.com/products-pipeline/kalvista-dme/ (accessed 2020-03-20).
    217. 217
      Murugesan, N.; Clermont, A. C.; Rushbrooke, L. J.; Robson, P. A.; Thoonen, R.; Pethen, S. J.; Hampton, S. L.; Feener, E. P. A novel oral plasma kallikrein (PKal) inhibitor KV123833 blocks VEGF-mediated retinal vascular hyperpermeability in a murine model of retinal edema. Invest. Ophthal. Vis. Sc. 2018, 59, 3464
    218. 218
      Bhatwadekar, A. D.; Kansara, V. S.; Ciulla, T. A. Investigational plasma kallikrein inhibitors for the treatment of diabetic macular edema: an expert assessment. Expert Opin. Invest. Drugs 2020, 29, 237244,  DOI: 10.1080/13543784.2020.1723078
    219. 219
      Novel Oral Plasma Kallikrein (PKa) Inhibitors KV998052 and KV998054 Ameliorate VEGF-Induced Retinal Thickening in a Murine Model of Retinal Edema; KalVista, 2019; https://www.kalvista.com/healthcare-providers/publications/ (accesed 2020-03-15).
    220. 220
      KalVista Pharmaceuticals Announces Collaboration with Merck; Business Wire, 2017; https://www.businesswire.com/news/home/20171010005129/en/KalVista-Pharmaceuticals-Announces-Collaboration-Merck/ (accessed 2020-03-20).
    221. 221
      KalVista Plans to Continue Work on Diabetic Macular Edema After Merck Walks Away from Deal; BioSpace, 2020; https://www.biospace.com/article/merck-walks-away-from-kalvista-option-deal/ (accessed 2020-03-20).
    222. 222
      Oxurion NV Reports Additional Positive Topline Data from Phase 1 with THR-149, a Novel, Potent Plasma Kallikrein Inhibitor for DME; Global Newswire, 2019; https://www.globenewswire.com/news-release/2019/09/09/1912924/0/en/Oxurion-NV-Reports-Additional-Positive-Topline-Data-from-Phase-1-with-THR-149-a-Novel-Potent-Plasma-Kallikrein-Inhibitor-for-DME.html/ (accessed 2020-03-20).
    223. 223
      Phipps, J. A.; Clermont, A. C.; Sinha, S.; Chilcote, T. J.; Bursell, S. E.; Feener, E. P. Plasma kallikrein mediates angiotensin II Type 1 receptor–stimulated retinal vascular permeability. Hypertension 2009, 53, 175181,  DOI: 10.1161/HYPERTENSIONAHA.108.117663
    224. 224
      Calton, M. A.; Ma, J. A.; Chang, E.; Litt, J. L.; Chang, S. S.; Estiarte, M. A.; Shiau, T. P.; Datta, A.; Kita, D. B. An orally dosed plasma kallikrein inhibitor decreases retinal vascular permeability in a rat model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018, 59, 3576
    225. 225
      (a) The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international dry eye workshop. Ocul. Surf. 2007, 5, 93107. DOI: 10.1016/S1542-0124(12)70082-4
      (b) Facts About Dry Eye; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/dryeye/dryeye/ (accessed 2019-01-29).
      (c) Hessen, A. W.; Akpek, E. K. Dry eye: an inflammatory ocular disease. J. Ophthalmic Vis. Res. 2014, 9, 240250
    226. 226
      (a) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International dry eye workshop. Ocul. Surf. 2007, 5, 7592. DOI: 10.1016/S1542-0124(12)70081-2
      (b) Clayton, J. A. Dry eye. N. Engl. J. Med. 2018, 378, 22122223,  DOI: 10.1056/NEJMra1407936 .
      (c) Hartstein, I.; Khwarg, S.; Przydryga, J. An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult population. Curr. Med. Res. Opin. 2005, 21, 255260,  DOI: 10.1185/030079905X26252 .
      (d) Bremond-Gignac, D.; Gicquel, J. J.; Chiambaretta, F. Pharmacokinetic evaluation of diquafosol tetrasodium for the treatment of Sjogren’s syndrome. Expert Opin. Drug Metab. Toxicol. 2014, 10, 905913,  DOI: 10.1517/17425255.2014.915026 .
      (e) Lim, A.; Wenk, M. R.; Tong, L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol. Med. 2015, 21, 736748,  DOI: 10.1016/j.molmed.2015.10.001 .
      (f) Narayanaswamy, A.; Leung, C. K.; Istiantoro, D. V.; Perera, S. A.; Ho, C. L.; Nongpiur, M. E.; Baskaran, M.; Htoon, H. M.; Wong, T. T.; Goh, D.; Su, D. H.; Belkin, M.; Aung, T. Efficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trial. JAMA Ophthalmol 2015, 133, 206212,  DOI: 10.1001/jamaophthalmol.2014.4893
    227. 227
      (a) Sall, K.; Stevenson, O. D.; Mundorf, T. K.; Reis, B. L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000, 107, 631639,  DOI: 10.1016/S0161-6420(99)00176-1 .
      (b) FDA Approves New Medication for Dry Eye Disease; US Food and Drug Administration, 2017; https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-dry-eye-disease/ (accessed 2019-02-21).
    228. 228
      Lee, Y. B.; Koh, J. W.; Hyon, J. Y.; Wee, W. R.; Kim, J. J.; Shin, Y. J. Sleep deprivation reduces tear secretion and impairs the tear film. Invest. Ophthalmol. Visual Sci. 2014, 55, 35253531,  DOI: 10.1167/iovs.14-13881
    229. 229
      Meibomian Gland Dysfunction (MGD); American Academy of Ophthalmology, 2019; https://eyewiki.aao.org/Meibomian_Gland_Dysfunction_(MGD) (accessed 2019-01-20).
    230. 230
      Rocha, E. M.; Wickham, L. A.; da Silveira, L. A.; Krenzer; Yu; Toda; Sullivan, D. A.; Sullivan, B. D. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br. J. Ophthalmol. 2000, 84, 7684,  DOI: 10.1136/bjo.84.1.76
    231. 231
      Haber, S. L.; Benson, V.; Buckway, C. J.; Gonzales, J. M.; Romanet, D.; Scholes, B. Lifitegrast: a novel drug for patients with dry eye disease. Ther. Adv. Ophthalmol. 2019, 11, 2515841419870366,  DOI: 10.1177/2515841419870366
    232. 232
      (a) Facts About Cataract; National Eye Institute: Bethesda, MD, 2019; https://nei.nih.gov/health/cataract/cataract_facts/ (accessed Jan 21, 2019).
      (b) Gimbel, H. V.; Dardzhikova, A. A. Consequences of waiting for cataract surgery. Curr. Opin. Ophthalmol. 2011, 22, 2830,  DOI: 10.1097/ICU.0b013e328341425d .
      (c) Priority Eye Diseases; World Health Organization, 2019; http://www9.who.int/blindness/causes/priority/en/ (accessed 2019-04-31).
    233. 233
      (a) Reddy, S. C. Electric cataract: a case report and review of the literature. Eur. J. Ophthalmol. 1999, 9, 134138,  DOI: 10.1177/112067219900900211 .
      (b) Ram, J.; Gupta, R. Petaloid Cataract. N. Engl. J. Med. 2016, 374, e22,  DOI: 10.1056/NEJMicm1507349 .
      (c) Hejtmancik, J. F.; Smaoui, N. Molecular genetics of cataract. Dev. Ophthalmol. 2003, 37, 6782,  DOI: 10.1159/000072039
    234. 234
      (a) Yu, J.; Asche, C. V.; Fairchild, C. J. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea 2011, 30, 379387,  DOI: 10.1097/ICO.0b013e3181f7f363 .
      (b) Bollinger, K. E.; Langston, R. H. What can patients expect from cataract surgery. Cleve Clin. J. Med. 2008, 75, 193196,  DOI: 10.3949/ccjm.75.3.193 .
      (c) Alshamrani, A. Z. Cataracts pathophysiology and managements. Egypt. J. Hosp. Med. 2018, 70, 151154,  DOI: 10.12816/0042978
    235. 235
      Davis, G. The evolution of cataract surgery. Mol. Med. 2016, 113, 5862
    236. 236
      Liu, Y. C.; Wilkins, M.; Kim, T.; Malyugin, B.; Mehta, J. S. Cataracts. Lancet 2017, 390, 600612,  DOI: 10.1016/S0140-6736(17)30544-5
    237. 237
      (a) Eisenberg, J. S. Are premium IOLS set to breakout? the market forces that have held them back may be about the change. Ophthalmol. Manage. 2013, 17, 3638.
      (b) Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 10881097,  DOI: 10.1016/j.jcrs.2015.04.005
    238. 238
      (a) Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 3539,  DOI: 10.1097/ICU.0000000000000016 .
      (b) Chen, X.; Yuan, F.; Wu, L. Meta-analysis of intraocular lens power calculation after laser refractive surgery in myopic eyes. J. Cataract Refractive Surg. 2016, 42, 163170,  DOI: 10.1016/j.jcrs.2015.12.005
    239. 239
      Mcgoldrick, K. E. Cataract extraction. In Decision Making in Anesthesiology: An Algorithm Approach, 4th ed..; Mosby/Elsevier: Maryland Heights, MO, 2007; pp 518519.
    240. 240
      (a) Zaczek, A.; Olivestedt, G.; Zetterström, C. Visual outcome after phacoemulsification and IOL implantation in diabetic patients. Br. J. Ophthalmol. 1999, 83, 10361041,  DOI: 10.1136/bjo.83.9.1036 .
      (b) Alezzandrini, A.; Arevalo, J. F. Phacoemulsification and pars plana vitrectomy. Retina Today 2010, 3437
    241. 241
      Shi, C.; Yuan, J.; Zee, B. Pain perception of the first eye versus the second eye during phacoemulsification under local anesthesia for patients going through cataract surgery: a systematic review and meta-analysis. J. Ophthalmol. 2019, 2019, 4106893,  DOI: 10.1155/2019/4106893
    242. 242
      McMonnies, C. W. The potential role of neuropathic mechanisms in dry eye syndromes. J. Optom. 2017, 10, 513,  DOI: 10.1016/j.optom.2016.06.002
    243. 243
      Asbell, P. A.; Dualan, I.; Mindel, J.; Brocks, D.; Ahmad, M.; Epstein, S. Age-related cataract. Lancet 2005, 365, 599609,  DOI: 10.1016/S0140-6736(05)70803-5
    244. 244
      Rong, X.; He, W.; Zhu, Q.; Qian, D.; Lu, Y.; Zhu, X. Intraocular lens power calculation in eyes with extreme myopia: Comparison of Barrett Universal II, Haigis, and Olsen formulas. J. Cataract Refractive Surg. 2019, 45, 732737,  DOI: 10.1016/j.jcrs.2018.12.025
    245. 245
      Khandelwal, S. S.; Jun, J. J.; Mak, S.; Booth, M. S.; Shekelle, P. G. Effectiveness of multifocal and monofocal intraocular lenses for cataract surgery and lens replacement: a systematic review and meta-analysis. Graefe's Arch. Clin. Exp. Ophthalmol. 2019, 257, 863875,  DOI: 10.1007/s00417-018-04218-6
    246. 246
      Schuster, A. K.; Tesarz, J.; Vossmerbaeumer, U. Ocular wavefront analysis of aspheric compared with spherical monofocal intraocular lenses in cataract surgery: systematic review with meta-analysis. J. Cataract Refractive Surg. 2015, 41, 10881097,  DOI: 10.1016/j.jcrs.2015.04.005
    247. 247
      Lai, E.; Levine, B.; Ciralsky, J. Ultraviolet-blocking intraocular lenses: fact or fiction. Curr. Opin. Ophthalmol. 2014, 25, 3539,  DOI: 10.1097/ICU.0000000000000016
    248. 248
      van Kooten, T. G.; Koopmans, S. A.; Terwee, T.; Langner, S.; Stachs, O.; Guthoff, R. F. Long-term prevention of capsular opacification after lens-refilling surgery in a rabbit model. Acta Ophthalmol. 2019, 97, e860e870,  DOI: 10.1111/aos.14096
    249. 249
      Donaldson, K. E.; Braga-Mele, R.; Cabot, F.; Davidson, R.; Dhaliwal, D. K.; Hamilton, R.; Jackson, M.; Patterson, L.; Stonecipher, K.; Yoo, H. Femtosecond laser-assisted cataract surgery. J. Cataract Refractive Surg. 2013, 39, 17531763,  DOI: 10.1016/j.jcrs.2013.09.002
    250. 250
      Karahan, E.; Er, D.; Kaynak, S. An Overview of Nd: YAG laser capsulotomy. Med. Hypothesis Discovery Innov. Ophthalmol. 2014, 3, 4550
    251. 251
      Ntsoane, M. D.; Oduntan, O. A.; Mpolokeng, B. L. Utilisation of public eye care services by the rural community residents in the Capricorn district, Limpopo Province, South Africa. African J. Prim. Health Care Fam. Med. 2012, 4, a412,  DOI: 10.4102/phcfm.v4i1.412
    252. 252
      Rabiu, M. M. Cataract blindness and barriers to uptake of cataract surgery in a rural community of northern Nigeria. Br. J. Ophthalmol. 2001, 85, 776780,  DOI: 10.1136/bjo.85.7.776
    253. 253
      Geneau, R.; Massae, P.; Courtright, P.; Lewallen, S. Using qualitative methods to understand the determinants of patients’ willingness to pay for cataract surgery: a study in Tanzania. Social science & medicine 2008, 66, 558568,  DOI: 10.1016/j.socscimed.2007.09.016
    254. 254
      Ntsoane, M.; Oduntan, O. A review of factors influencing the utilization of eye care services. Afr. Vis. Eye Health 2010, 69, 182192,  DOI: 10.4102/aveh.v69i4.143
    255. 255
      Fadamiro, C.; Ajite, K. Barriers to utilization of cataract surgical services in ekiti state, south western nigeria. Nig. J. Clin. Prac. 2017, 20, 783786
    256. 256
      Atiyeh, B. S.; Gunn, S. W. A.; Hayek, S. N. Provision of essential surgery in remote and rural areas of developed as well as low and middle income countries. Int. J. Sur. 2010, 8, 581585,  DOI: 10.1016/j.ijsu.2010.07.291
    257. 257
      Makley, L. N.; McMenimen, K. A.; DeVree, B. T.; Goldman, J. W.; McGlasson, B. N.; Rajagopal, P.; Dunyak, B. M.; McQuade, T. J.; Thompson, A. D.; Sunahara, R.; Klevit, R. E.; Andley, U. P.; Gestwicki, J. E. Pharmacological chaperone for α-Crystallin partially restores transparency in cataract models. Science 2015, 350, 674677,  DOI: 10.1126/science.aac9145
    258. 258
      Molnar, K. S.; Dunyak, B. M.; Su, B.; Izrayelit, Y.; McGlasson-Naumann, B.; Hamilton, P. D.; Qian, M.; Covey, D. F.; Gestwicki, J. E.; Makley, L. H.; Andley, U. P. Mechanism of action of VP1–001 in cryAB(R120G)- associated and age-related cataracts. Invest. Ophthalmol. Visual Sci. 2019, 60, 33203321,  DOI: 10.1167/iovs.18-25647
    259. 259
      New Drugs You May Have Missed. Review of Cornea and Contact Lenses 2014, https://www.reviewofcontactlenses.com/article/new-drugs-you-may-have-missed/ (accessed 2020-03-20).
    260. 260
      Campos-Sandoval, J. A.; Redondo, C.; Kinsella, G. K.; Pal, A.; Jones, G.; Eyre, G. S.; Hirst, S. C.; Findlay, J. B. Fenretinide derivatives act as disrupters of interactions of serum retinol binding protein (sRBP) with transthyretin and the sRBP receptor. J. Med. Chem. 2011, 54, 43784387,  DOI: 10.1021/jm200256g
    261. 261
      Cioffi, C. L.; Dobri, N.; Freeman, E. E.; Conlon, M. P.; Chen, P.; Stafford, D. G.; Schwarz, D. M.; Golden, K. C.; Zhu, L.; Kitchen, D. B.; Barnes, K. D.; Racz, B.; Qin, Q.; Michelotti, E.; Cywin, C. L.; Martin, W. H.; Pearson, P. G.; Johnson, G.; Petrukhin, K. Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J. Med. Chem. 2014, 57, 77317757,  DOI: 10.1021/jm5010013
    262. 262
      Wang, Y.; Connors, R.; Fan, P.; Wang, X.; Wang, Z.; Liu, J.; Kayser, F.; Medina, J. C.; Johnstone, S.; Xu, H.; Thibault, S.; Walker, N.; Conn, M.; Zhang, Y.; Liu, Q.; Grillo, M. P.; Motani, A.; Coward, P.; Wang, Z. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4. Bioorg. Med. Chem. Lett. 2014, 24, 28852891,  DOI: 10.1016/j.bmcl.2014.04.089
    263. 263
      Stanton, C. M.; Yates, J. R.; den Hollander, A. I.; Seddon, J. M.; Swaroop, A.; Stambolian, D.; Fauser, S.; Hoyng, C.; Yu, Y.; Atsuhiro, K.; Branham, K.; Othman, M.; Chen, W.; Kortvely, E.; Chalmers, K.; Hayward, C.; Moore, A. T.; Dhillon, B.; Ueffing, M.; Wright, A. F. Complement factor D in age-related macular degeneration. Invest. Ophthalmol. Visual Sci. 2011, 52, 88288834,  DOI: 10.1167/iovs.11-7933
    264. 264
      Vulpetti, A.; Ostermann, N.; Randl, S.; Yoon, T.; Mac Sweeney, A.; Cumin, F.; Lorthiois, E.; Rudisser, S.; Erbel, P.; Maibaum, J. Discovery and design of first benzylamine-based ligands binding to an unlocked conformation of the complement factor D. ACS Med. Chem. Lett. 2018, 9, 490495,  DOI: 10.1021/acsmedchemlett.8b00104
    265. 265
      Zhang, M.; Yang, X. Y.; Tang, W.; Groeneveld, T. W. L.; He, P. L.; Zhu, F. H.; Li, J.; Lu, W.; Blom, A. M.; Zuo, J. P.; Nan, F. J. Discovery and structural modification of 1-Phenyl-3-(1-phenylethyl)urea derivatives as inhibitors of complement. ACS Med. Chem. Lett. 2012, 3, 317321,  DOI: 10.1021/ml300005w
    266. 266
      Meredith, E. L.; Mainolfi, N.; Poor, S.; Qiu, Y.; Miranda, K.; Powers, J.; Liu, D.; Ma, F.; Solovay, C.; Rao, C.; Johnson, L.; Ji, N.; Artman, G.; Hardegger, L.; Hanks, S.; Shen, S.; Woolfenden, A.; Fassbender, E.; Sivak, J. M.; Zhang, Y.; Long, D.; Cepeda, R.; Liu, F.; Hosagrahara, V. P.; Lee, W.; Tarsa, P.; Anderson, K.; Elliott, J.; Jaffee, B. Discovery of oral VEGFR2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 2015, 58, 92739286,  DOI: 10.1021/acs.jmedchem.5b01227
    267. 267
      Adams, C. M.; Anderson, K.; Artman, G.; Bizec, J. C.; Cepeda, R.; Elliott, J.; Fassbender, E.; Ghosh, M.; Hanks, S.; Hardegger, L. A.; Hosagrahara, V. P.; Jaffee, B.; Jendza, K.; Ji, N.; Johnson, L.; Lee, W.; Liu, D.; Liu, F.; Long, D.; Ma, L. F.; Mainolfi, N.; Meredith, E. L.; Miranda, K.; Peng, Y.; Poor, S.; Powers, J.; Qiu, Y.; Rao, C.; Shen, S.; Sivak, J. M.; Solovay, C.; Tarsa, P.; Woolfenden, A.; Zhang, C.; Zhang, Y. The discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 inhibitor specifically designed for topical ocular delivery, as a therapy for neovascular age-related macular degeneration. J. Med. Chem. 2018, 61, 16221635,  DOI: 10.1021/acs.jmedchem.7b01731
    268. 268
      Basavarajappa, H. D.; Lee, B.; Lee, H.; Sulaiman, R. S.; An, H.; Magaña, C.; Shadmand, M.; Vayl, A.; Rajashekhar, G.; Kim, E. Y.; Suh, Y. G.; Lee, K.; Seo, S. Y.; Corson, T. W. Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization. J. Med. Chem. 2015, 58, 50155027,  DOI: 10.1021/acs.jmedchem.5b00449
    269. 269
      Palanki, M. S. S.; Akiyama, H.; Campochiaro, P.; Cao, J.; Chow, C. P.; Dellamary, L.; Doukas, J.; Fine, R.; Gritzen, C.; Hood, J. D.; Hu, S.; Kachi, S.; Kang, X.; Klebansky, B.; Kousba, A.; Lohse, D.; Mak, C. C.; Martin, M.; McPherson, A.; Pathak, V. P.; Renick, J.; Soll, R.; Umeda, N.; Yee, S.; Yokoi, K.; Zeng, B.; Zhu, H.; Noronha, G. Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl Benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J. Med. Chem. 2008, 51, 15461559,  DOI: 10.1021/jm7011276
    270. 270
      Olivieri, M.; Amata, E.; Vinciguerra, S.; Fiorito, J.; Giurdanella, G.; Drago, F.; Caporarello, N.; Prezzavento, O.; Arena, E.; Salerno, L.; Rescifina, A.; Lupo, G.; Anfuso, C. D.; Marrazzo, A. Antiangiogenic effect of (±)-haloperidol metabolite II valproate ester [(±)-MRJF22] in human microvascular retinal endothelial cells. J. Med. Chem. 2016, 59, 99609966,  DOI: 10.1021/acs.jmedchem.6b01039
    271. 271
      Papadaki, T.; Tsilimbaris, M.; Thermos, K.; Karavellas, M.; Samonakis, D.; Papapdakis, A.; Linardakis, M.; Kouromalis, E.; Pallikaris, I. The role of lanreotide in the treatment of choroidal neovascularization secondary to age-related macular degeneration: a pilot clinical trial. Retina 2003, 23, 800807,  DOI: 10.1097/00006982-200312000-00010
    272. 272
      Wolkenberg, S. E.; Zhao, Z.; Thut, C.; Maxwell, W. J.; McDonald, T. P.; Kinose, F.; Reilly, M.; Lindsley, C. W.; Hartman, G. D. Design, synthesis, and evaluation of novel 3, 6-Diaryl-4- amino alkoxy quinolines as selective agonists of somatostatin receptor subtype 2. J. Med. Chem. 2011, 54, 23512358,  DOI: 10.1021/jm101501b
    273. 273
      Arjamaa, O.; Nikinmaa, M.; Salminen, A.; Kaarniranta, K. Regulatory role of HIF-1 α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res. Rev. 2009, 8, 349358,  DOI: 10.1016/j.arr.2009.06.002
    274. 274
      Oh, S. H.; Woo, J. K.; Yazici, Y. D.; Myers, J. N.; Kim, W. Y.; Jin, Q.; Hong, S. S.; Park, H. J.; Suh, Y. G.; Kim, K. W.; Hong, W. K.; Lee, H. Y. Structural basis for depletion of heat shock protein 90 client proteins by deguelin. J. Natl. Canc. Inst. 2007, 99, 949961,  DOI: 10.1093/jnci/djm007
    275. 275
      (a) Lee, S.; An, H.; Chang, D. J.; Jang, J.; Kim, K.; Sim, J.; Lee, J.; Suh, Y. G. Total synthesis of (−)-deguelin via an iterative pyran-ring formation strategy. Chem. Commun. 2015, 51, 90269029,  DOI: 10.1039/C5CC02215K .
      (b) Chang, D. J.; An, H.; Kim, K. S.; Kim, H. H.; Jung, J.; Lee, J. M.; Kim, N. J.; Han, Y. T.; Yun, H.; Lee, S.; Lee, G.; Lee, S.; Lee, J. S.; Cha, J. H.; Park, J. H.; Park, J. W.; Lee, S. C.; Kim, S. G.; Kim, J. H.; Lee, H. Y.; Kim, K. W.; Suh, Y. G. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J. Med. Chem. 2012, 55, 1086310884,  DOI: 10.1021/jm301488q
    276. 276
      An, H.; Lee, S.; Lee, J. M.; Jo, D. H.; Kim, J.; Jeong, Y. S.; Heo, M. J.; Cho, C. S.; Choi, H.; Seo, J. H.; Hwang, S.; Lim, J.; Kim, T.; Jun, H. O.; Sim, J.; Lim, C.; Hur, J.; Ahn, J.; Kim, H. S.; Seo, S. Y.; Na, Y.; Kim, S. H.; Lee, J.; Lee, J.; Chung, S. J.; Kim, Y. M.; Kim, K. W.; Kim, S. G.; Kim, J. H.; Suh, Y. G. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy. J. Med. Chem. 2018, 61, 92669286,  DOI: 10.1021/acs.jmedchem.8b00971
    277. 277
      Jin, H.; Randazzo, J.; Zhang, P.; Kador, P. F. Multifunctional antioxidants for the treatment of age-related diseases. J. Med. Chem. 2010, 53, 11171127,  DOI: 10.1021/jm901381j
    278. 278
      Joshi, D.; Field, J.; Murphy, J.; Abdelrahim, M.; Schönherr, H.; Sparrow, J. R.; Ellestad, E. G.; Nakanishi, K.; Zask, A. Synthesis of antioxidants for prevention of age-related macular degeneration. J. Nat. Prod. 2013, 76, 450454,  DOI: 10.1021/np300769c
    279. 279
      Deng, H.; Li, T.; Xie, J.; Huang, N.; Gu, Y.; Zhao, J. Synthesis and bio-evaluation of novel hypocrellin derivatives. potential photosensitizers for photodynamic therapy of age-related macular degeneration. Dyes Pigm. 2013, 99, 930939,  DOI: 10.1016/j.dyepig.2013.06.037
    280. 280
      Carta, F.; Aggarwal, M.; Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C. T. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in Vivo. J. Med. Chem. 2012, 55, 17211730,  DOI: 10.1021/jm300031j
    281. 281
      Carta, F.; Akdemir, A.; Scozzafava, A.; Masini, E.; Supuran, C. T. Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. J. Med. Chem. 2013, 56, 46914700,  DOI: 10.1021/jm400414j
    282. 282
      Vullo, D.; Durante, M.; Di Leva, F. S.; Cosconati, S.; Masini, E.; Scozzafava, A.; Novellino, E.; Supuran, C. T.; Carta, F. Monothiocarbamates strongly inhibit carbonic anhydrases in vitro and possess intraocular pressure lowering activity in an animal model of glaucoma. J. Med. Chem. 2016, 59, 58575867,  DOI: 10.1021/acs.jmedchem.6b00462
    283. 283
      Bozdag, M.; Pinard, M.; Carta, F.; Masini, E.; Scozzafava, A.; McKenna, R.; Supuran, C. T. A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects. J. Med. Chem. 2014, 57, 96739686,  DOI: 10.1021/jm501497m
    284. 284
      Bozdag, M.; Ferraroni, M.; Carta, F.; Vullo, D.; Lucarini, L.; Orlandini, E.; Rossello, A.; Nuti, E.; Scozzafava, A.; Masini, E.; Supuran, C. T. Structural insights on carbonic anhydrase inhibitory action, isoform selectivity, and potency of sulfonamides and coumarins incorporating arylsulfonylureido groups. J. Med. Chem. 2014, 57, 91529167,  DOI: 10.1021/jm501314c
    285. 285
      Carta, F.; Osman, S. M.; Vullo, D.; Gullotto, A.; Winum, J. Y.; AlOthman, Z.; Masini, E.; Supuran, C. T. Poly(amidoamine) dendrimers with carbonic anhydrase inhibitory activity and antiglaucoma action. J. Med. Chem. 2015, 58, 40394045,  DOI: 10.1021/acs.jmedchem.5b00383
    286. 286
      Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.; Supuran, C. T.; Poulsen, S. A. A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click- tailing. J. Med. Chem. 2006, 49, 65396548,  DOI: 10.1021/jm060967z
    287. 287
      Pacchiano, F.; Carta, F.; McDonald, P. C.; Lou, Y.; Vullo, D.; Scozzafava, A.; Dedhar, S.; Supuran, C. T. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J. Med. Chem. 2011, 54, 18961902,  DOI: 10.1021/jm101541x
    288. 288
      Nocentini, A.; Ferraroni, M.; Carta, F.; Ceruso, M.; Gratteri, P.; Lanzi, C.; Masini, E.; Supuran, C. T. Benzenesulfonamides incorporating flexible triazole moieties are highly effective carbonic anhydrase inhibitors: synthesis and kinetic, crystallographic, computational, and intraocular pressure lowering investigations. J. Med. Chem. 2016, 59, 1069210704,  DOI: 10.1021/acs.jmedchem.6b01389
    289. 289
      Huang, Q.; Rui, E. Y.; Cobbs, M.; Dinh, D. M.; Gukasyan, H. J.; Lafontaine, J. A.; Mehta, S.; Patterson, B. D.; Rewolinski, D. A.; Richardson, P. F.; Edwards, M. P. Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure. J. Med. Chem. 2015, 58, 28212833,  DOI: 10.1021/acs.jmedchem.5b00043
    290. 290
      Yin, Y.; Lin, L.; Ruiz, C.; Khan, S.; Cameron, M. D.; Grant, W.; Pocas, J.; Eid, N.; Park, H.; Schröter, T.; Lograsso, P. V.; Feng, Y. Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors. J. Med. Chem. 2013, 56, 35683581,  DOI: 10.1021/jm400062r
    291. 291
      Fang, X.; Yin, Y.; Chen, Y. T.; Yao, L.; Wang, B.; Cameron, M. D.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; LoGrasso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors. J. Med. Chem. 2010, 53, 57275737,  DOI: 10.1021/jm100579r
    292. 292
      Wu, F.; Buttner, F.; Chen, R.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem, M.; Kerr, S.; Kugler, S.; Paw, Z.; Prokopowicz, A.; Shih, C.; Snow, R.; Young, E.; Cywin, C. Substituted 2H-isoquinolin-1-one as potent Rho-kinase inhibitors. part 1: hit-to-lead account. Bioorg. Med. Chem. Lett. 2010, 20, 32353239,  DOI: 10.1016/j.bmcl.2010.04.070
    293. 293
      Doe, C.; Bentley, R.; Behm, D. J.; Lafferty, R.; Stavenger, R.; Jung, D.; Bamford, M.; Panchal, T.; Grygielko, E.; Wright, L. L.; Smith, G. K.; Chen, Z.; Webb, C.; Khandekar, S.; Yi, T.; Kirkpatrick, R.; Dul, E.; Jolivette, L.; Marino, J. P.; Willette, R.; Lee, D.; Hu, E. J. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J. Pharmacol. Exp. Ther. 2007, 320, 8998,  DOI: 10.1124/jpet.106.110635
    294. 294
      Ginn, J. D.; Bosanac, T.; Chen, R.; Cywin, C.; Hickey, E.; Kashem, M.; Kerr, S.; Kugler, S.; Li, X.; Prokopowicz, A.; Schlyer, S.; Smith, J. D.; Turner, M. R.; Wu, F.; Young, E. R. Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats. Bioorg. Med. Chem. Lett. 2010, 20, 51535156,  DOI: 10.1016/j.bmcl.2010.07.014
    295. 295
      Li, R.; Martin, M. P.; Liu, Y.; Wang, B.; Patel, R. A.; Zhu, J. Y.; Sun, N.; Pireddu, R.; Lawrence, N. J.; Li, J.; Haura, E. B.; Sung, S. S.; Guida, W. C.; Schonbrunn, E.; Sebti, S. M. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J. Med. Chem. 2012, 55, 24742478,  DOI: 10.1021/jm201289r
    296. 296
      Chen, Y. T.; Bannister, T. D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M. D.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 64066409,  DOI: 10.1016/j.bmcl.2008.10.080
    297. 297
      Boland, S.; Defert, O.; Alen, J.; Bourin, A.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Van de Velde, S.; Stalmans, I.; Leysen, D. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 64426446,  DOI: 10.1016/j.bmcl.2013.09.040
    298. 298
      Blangetti, M.; Rolando, B.; Marini, E.; Chegaev, K.; Guglielmo, S.; Lazzarato, L.; Lucarini, L.; Masini, E.; Fruttero, R. Gem-dinitroalkyl benzenes: a novel class of IOP-lowering agents for the treatment of ocular hypertension. ACS Med. Chem. Lett. 2017, 8, 10541059,  DOI: 10.1021/acsmedchemlett.7b00264
    299. 299
      Ehara, T.; Adams, C. M.; Bevan, D.; Ji, N.; Meredith, E. L.; Belanger, D. B.; Powers, J.; Kato, M.; Solovay, C.; Liu, D.; Capparelli, M.; Bolduc, P.; Grob, J. E.; Daniels, M. H.; Ferrara, L.; Yang, L.; Li, B.; Towler, C. S.; Stacy, R. C.; Prasanna, G.; Mogi, M. The discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a soluble guanylate cyclase activator specifically designed for topical ocular delivery as a therapy for glaucoma. J. Med. Chem. 2018, 61, 25522570,  DOI: 10.1021/acs.jmedchem.8b00007
    300. 300
      (a) May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin, M. A.; Sharif, N. A. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A potent peripherally acting 5-HT 2 receptor agonist with ocular hypertensive activity. J. Med. Chem. 2006, 49, 318328,  DOI: 10.1021/jm050663x .
      (b) May, J. A.; Chen, H. H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A. A novel and selective 5-HT 2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9 dihydropyrano[3,2-e]indole. J. Med. Chem. 2003, 46, 41884195,  DOI: 10.1021/jm030205t
    301. 301
      May, J. A.; Sharif, N. A.; McLaughlin, M. A.; Chen, H. H.; Severns, B. S.; Kelly, C. R.; Holt, W. F.; Young, R.; Glennon, R. A.; Hellberg, M. R.; Dean, T. R. Ocular hypotensive response in nonhuman primates of(8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a selective 5-HT2 receptor agonist. J. Med. Chem. 2015, 58, 88188833,  DOI: 10.1021/acs.jmedchem.5b00857
    302. 302
      Chemerovski-Glikman, M.; Mimouni, M.; Dagan, Y.; Haj, E.; Vainer, I.; Allon, R.; Blumenthal, E. Z.; Adler-Abramovich, L.; Segal, D.; Gazit, E.; Zayit-Soudry, S. Rosmarinic acid restores complete transparency of sonicated human cataract ex Vivo and delays cataract formation in Vivo. Sci. Rep. 2018, 8, 9341,  DOI: 10.1038/s41598-018-27516-9
    303. 303
      Chang, K. C.; Li, L.; Sanborn, T. M.; Shieh, B.; Lenhart, P.; Ammar, D.; LaBarbera, D. V.; Petrash, J. M. Characterization of emodin as a therapeutic agent for diabetic cataract. J. Nat. Prod. 2016, 79, 14391444,  DOI: 10.1021/acs.jnatprod.6b00185
    304. 304
      Da Settimo, F.; Primofiore, G.; La Motta, C.; Sartini, S.; Taliani, S.; Simorini, F.; Marini, A. M.; Lavecchia, A.; Novellino, E.; Boldrini, E. Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors. J. Med. Chem. 2005, 48, 68976907,  DOI: 10.1021/jm050382p
    305. 305
      Teufel, D. P.; Bennett, G.; Harrison, H.; van Rietschoten, K.; Pavan, S.; Stace, C.; Le Floch, F.; Van Bergen, T.; Vermassen, E.; Barbeaux, P.; Hu, T. T.; Feyen, J. H. M.; Vanhove, M. Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J. Med. Chem. 2018, 61, 28232836,  DOI: 10.1021/acs.jmedchem.7b01625
    306. 306
      (a) Inoue, T.; Morita, M.; Tojo, T.; Yoshihara, K.; Nagashima, A.; Moritomo, A.; Ohkubo, M.; Miyake, H. Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema. Bioorg. Med. Chem. 2013, 21, 12191233,  DOI: 10.1016/j.bmc.2012.12.025 .
      (b) Inoue, T.; Morita, M.; Tojo, T.; Nagashima, A.; Moritomo, A.; Miyake, H. S. Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. Bioorg. Med. Chem. 2013, 21, 38733881,  DOI: 10.1016/j.bmc.2013.04.011
    307. 307
      González-Correa, J. A.; Rodríguez-Pérez, M. D.; Márquez-Estrada, L.; López-Villodres, J. A.; Reyes, J. J.; Rodriguez-Gutierrez, G.; Fernández-Bolaños, J.; De La Cruz, J. P. Neuroprotective effect of hydroxytyrosol in experimental diabetic retinopathy: relationship with cardiovascular biomarkers. J. Agric. Food Chem. 2018, 66, 637644,  DOI: 10.1021/acs.jafc.7b05063
    308. 308
      van Lier, J. E.; Tian, H.; Ali, H.; Cauchon, N.; Hasséssian, H. M. Trisulfonated porphyrazines: new photosensitizers for the treatment of retinal and subretinal edema. J. Med. Chem. 2009, 52, 41074110,  DOI: 10.1021/jm900350f
    309. 309
      Mores, A. M.; Casey, D.; Felix, C. M.; Phuan, P. W.; Verkman, A. S.; Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J. 2016, 30, 17891797,  DOI: 10.1096/fj.201500180
    310. 310
      Lee, S.; Phuan, P. W.; Felix, C. M.; Tan, J. A.; Levin, M. H.; Verkman, A. S. Nanomolar-potency aminophenyl-1,3,5-triazine activators of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel for prosecretory therapy of dry eye diseases. J. Med. Chem. 2017, 60, 12101218,  DOI: 10.1021/acs.jmedchem.6b01792
    311. 311
      Saxena, V.; Sadoqi, M.; Shao, J. Degradation kinetics of indocyanine green in aqueous solution. J. Pharm. Sci. 2003, 92, 20902097,  DOI: 10.1002/jps.10470
    312. 312
      Langhals, H.; Varja, A.; Laubichler, P.; Kernt, M.; Eibl, K.; Haritoglou, C. Cyanine dyes as optical contrast agents for ophthalmological surgery. J. Med. Chem. 2011, 54, 39033925,  DOI: 10.1021/jm2001986
    313. 313
      Myochin, T.; Hanaoka, K.; Komatsu, T.; Terai, T.; Nagano Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J. Am. Chem. Soc. 2012, 134, 1373013737,  DOI: 10.1021/ja303931b
    314. 314
      Simard, B.; Tomanek, B.; van Veggel, F. C.; Abulrob, A. Optimal dye-quencher pairs for the design of an ″activatable″ nanoprobe for optical imaging. Photochem. Photobiol. Sci. 2013, 12, 18241829,  DOI: 10.1039/c3pp50118c
    315. 315
      (a) Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharmacol. 2013, 2, 4764,  DOI: 10.5497/wjp.v2.i2.47 .
      (b) Kels, B. D.; Grzybowski, A.; Grant-Kels, J. M. Human ocular anatomy. Clin. Dermatol. 2015, 33, 140146,  DOI: 10.1016/j.clindermatol.2014.10.006 .
      (c) Kim, Y. C.; Chiang, B.; Wu, X.; Prausnitz, M. R. Ocular delivery of macromolecules. J. Controlled Release 2014, 190, 172181,  DOI: 10.1016/j.jconrel.2014.06.043
    316. 316
      Eljarrat-Binstock, E.; Domb, A. J. Iontophoresis: a non-invasive ocular drug delivery. J. Controlled Release 2006, 110, 479489,  DOI: 10.1016/j.jconrel.2005.09.049
    317. 317
      Ye, T.; Yuan, K.; Zhang, W.; Song, S.; Chen, F.; Yang, X.; Wang, S.; Bi, J.; Pan, W. Prodrugs incorporated into nanotechnology-based drug delivery systems for possible improvement in bioavailability of ocular drugs delivery. Asian J. Pharm. Sci. 2013, 8, 207217,  DOI: 10.1016/j.ajps.2013.09.002
    318. 318
      Higashiyama, M.; Tajika, T.; Inada, K.; Ohtori, A. Improvement of the ocular bioavailability of carteolol by ion pair. J. Ocul. Pharmacol. Ther. 2006, 22, 333339,  DOI: 10.1089/jop.2006.22.333
    319. 319
      Loftssona, T.; Järvinen, T. Cyclodextrins in ophthalmic drug delivery. Adv. Drug Delivery Rev. 1999, 36, 5979,  DOI: 10.1016/S0169-409X(98)00055-6
    320. 320
      Lach, J. L.; Huang, H. S.; Schoenwald, R. D. Corneal penetration behavior of β-blocking agents II: assessment of barrier contributions. J. Pharm. Sci. 1983, 72, 12721279,  DOI: 10.1002/jps.2600721109
    321. 321
      Wang, J.; Zhao, F.; Liu, R.; Chen, J.; Zhang, Q.; Lao, R.; Wang, Z.; Jin, X.; Liu, C. Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies. Int. J. Nanomed. 2017, 12, 81158127,  DOI: 10.2147/IJN.S139436
    322. 322
      Huang, A.; Tseng, S.; Kenyon, K. Paracellular permeability of corneal and conjunctival epithelia. Invest. Ophth. Vis. Sc. 1989, 30, 684689
    323. 323
      Olsen, T. W.; Aaberg, S. Y.; Geroski, D. H.; Edelhauser, H. F. Human sclera: thickness and surface area. Am. J. Ophthalmol. 1998, 125, 237241,  DOI: 10.1016/S0002-9394(99)80096-8
    324. 324
      Cruysberg, L. P.; Nuijts, R. M.; Geroski, D. H.; Koole, L. H.; Hendrikse, F.; Edelhauser, H. F. In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J. Ocul. Pharmacol. Ther. 2002, 18, 559569,  DOI: 10.1089/108076802321021108
    325. 325
      Ambati, J.; Adamis, A. P. Transscleral drug delivery to the retina and choroid. Prog. Retinal Eye Res. 2002, 21, 145151,  DOI: 10.1016/S1350-9462(01)00018-0
    326. 326
      Maurice, D.; Polgar, J. Diffusion across the sclera. Exp. Eye Res. 1977, 25, 577582,  DOI: 10.1016/0014-4835(77)90136-1
    327. 327
      Ambati, J.; Canakis, C. S.; Miller, J. W.; Gragoudas, E. S.; Edwards, A.; Weissgold, D. J.; Kim, I.; Delori, F. C.; Adamis, A. P. Diffusion of high molecular weight compounds through sclera. Invest. Ophthal. Vis. Sci. 2000, 41, 11811185
    328. 328
      Pescina, S.; Govoni, P.; Antopolsky, M.; Murtomaki, L.; Padula, C.; Santi, P.; Nicoli, S. Permeation of proteins, oligonucleotide and dextrans across ocular tissues: experimental studies and a literature update. J. Pharm. Sci. 2015, 104, 21902202,  DOI: 10.1002/jps.24465
    329. 329
      Kamei, M.; Misono, K.; Lewis, H. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am. J. Ophthalmol. 1999, 128, 739746,  DOI: 10.1016/S0002-9394(99)00239-1
    330. 330
      Jackson, T. L.; Antcliff, R. J.; Hillenkamp, J.; Marshall, J. Human retinal molecular weight exclusion limit and estimate of species variation. Invest. Ophthalmol. Visual Sci. 2003, 44, 21412146,  DOI: 10.1167/iovs.02-1027
    331. 331
      Marmor, M. F.; Negi, A.; Maurice, D. M. Kinetics of macromolecules injected into the subretinal space. Exp. Eye Res. 1985, 40, 687696,  DOI: 10.1016/0014-4835(85)90138-1
    332. 332
      Runkle, E. A.; Antonetti, D. A. The blood-retinal barrier: structure and functional significance. Methods Mol. Biol. 2011, 686, 133148,  DOI: 10.1007/978-1-60761-938-3_5
    333. 333
      Hammes, H. P.; Lin, J.; Renner, O.; Shani, M.; Lundqvist, A.; Betsholtz, C.; Brownlee, M.; Deutsch, U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51, 31073112,  DOI: 10.2337/diabetes.51.10.3107
    334. 334
      Motieju̅naitė, R.; Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 2008, 86, 171177,  DOI: 10.1016/j.exer.2007.10.013
    335. 335
      Pitkänen, L.; Ranta, V. P.; Moilanen, H.; Urtti, A. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest. Ophthalmol. Visual Sci. 2005, 46, 641646,  DOI: 10.1167/iovs.04-1051
    336. 336
      (a) Gaudana, R.; Ananthula, H. K.; Parenky, A.; Mitra, A. K. Ocular drug delivery. AAPS J. 2010, 12, 348360,  DOI: 10.1208/s12248-010-9183-3 .
      (b) Geroski, D. H.; Edelhauser, H. F. Drug delivery for posterior segment eye disease. Invest. Ophthalmol. Vis. Sci. 2000, 41, 961964.
      (c) Hornof, M.; Toropainen, E.; Urtti, A. cell culture models of the ocular barriers. Eur. J. Pharm. Biopharm. 2005, 60, 207225,  DOI: 10.1016/j.ejpb.2005.01.009
    337. 337
      (a) Boddu, S. H.; Gunda, S.; Earla, R.; Mitra, A. K. Ocular microdialysis: a continuous sampling technique to study pharmacokinetics and pharmacodynamics in the eye. Bioanalysis 2010, 2, 487507,  DOI: 10.4155/bio.10.2 .
      (b) Kaur, I. P.; Kanwar, M. Ocular preparations: the formulation approach. Drug Dev. Ind. Pharm. 2002, 28, 473493,  DOI: 10.1081/DDC-120003445 .
      (c) Shirasaki, Y. Molecular design for enhancement of ocular penetration. J. Pharm. Sci. 2008, 97, 24622496,  DOI: 10.1002/jps.21200
    338. 338
      (a) She, S. C.; Steahly, L. P.; Moticka, E. J. Intracameral injection of allogeneic lymphocytes enhances corneal graft survival. Invest. Ophthalmol. Vis. Sci. 1990, 31, 19501956.
      (b) Lane, S. S.; Osher, R. H.; Masket, S.; Belani, S. Evaluation of the safety of prophylactic intracameral moxifloxacin in cataract surgery. J. Cataract Refractive Surg. 2008, 34, 14511459,  DOI: 10.1016/j.jcrs.2008.05.034 .
      (c) Braga-Mele, R.; Chang, D. F.; Henderson, B. A.; Mamalis, N.; Talley-Rostov, A. Intracameral antibiotics: safety, efficacy, and preparation. J. Cataract Refractive Surg. 2014, 40, 21342142,  DOI: 10.1016/j.jcrs.2014.10.010
    339. 339
      (a) Duvvuri, S.; Majumdar, S.; Mitra, A. K. Drug delivery to the retina: challenges and opportunities. Expert Opin. Biol. Ther. 2003, 3, 4556,  DOI: 10.1517/14712598.3.1.45 .
      (b) Hsu, J. Drug delivery methods for posterior segment disease. Curr. Opin. Ophthalmol. 2007, 18, 235239,  DOI: 10.1097/ICU.0b013e3281108000 .
      (c) Holekamp, N. M. The vitreous gel: more than meets the eye. Am. J. Ophthalmol. 2010, 149, 3236,  DOI: 10.1016/j.ajo.2009.07.036
    340. 340
      (a) Hikichi, T.; Kado, M.; Yoshida, A. Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment in the rabbit. Retina 2000, 20, 195198,  DOI: 10.1097/00006982-200002000-00014 .
      (b) Martens, T. F.; Remaut, K.; Deschout, H.; Engbersen, J. F.; Hennink, W. E.; van Steenbergen, M. J.; Demeester, J.; De Smedt, S. C.; Braeckmans, K. Coating nanocarriers with hyaluronic acid facilitates intravitreal drug delivery for retinal gene therapy. J. Controlled Release 2015, 202, 8392,  DOI: 10.1016/j.jconrel.2015.01.030
    341. 341
      (a) Raghava, S.; Hammond, M.; Kompella, U. B. Periocular routes for retinal drug delivery. Expert Opin. Drug Delivery 2004, 1, 99114,  DOI: 10.1517/17425247.1.1.99 .
      (b) Janoria, K. G.; Gunda, S.; Boddu, S. H.; Mitra, A. K. Novel approaches to retinal drug delivery. Expert Opin. Drug Delivery 2007, 4, 371388,  DOI: 10.1517/17425247.4.4.371 .
      (c) Kim, S. H.; Galban, C. J.; Lutz, R. J.; Dedrick, R. L.; Csaky, K. G.; Lizak, M. J.; Wang, N. S.; Tansey, G.; Robinson, M. R. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging. Invest. Ophthalmol. Visual Sci. 2007, 48, 808814,  DOI: 10.1167/iovs.06-0670
    342. 342
      Hosoya, K. I.; Tomi, M. Advances in the cell biology of transport via the inner blood-retinal barrier: establishment of cell lines and transport functions. Biol. Pharm. Bull. 2005, 28, 18,  DOI: 10.1248/bpb.28.1
    343. 343
      Stewart, P.; Tuor, U. Blood-eye barriers in the rat: correlation of ultrastructure with function. J. Comp. Neurol. 1994, 340, 566576,  DOI: 10.1002/cne.903400409
    344. 344
      Toda, R.; Kawazu, K.; Oyabu, M.; Miyazaki, T.; Kiuchi, Y. Comparison of drug permeabilities across the blood–retinal barrier, blood–aqueous humor barrier, and blood–brain barrier. J. Pharm. Sci. 2011, 100, 39043911,  DOI: 10.1002/jps.22610
    345. 345
      Farkouh, A.; Frigo, P.; Czejka, M. Systemic side effects of eye drop: a pharmacokinetic perspective. Clin. Ophthalmol. 2016, 10, 24332441,  DOI: 10.2147/OPTH.S118409
    346. 346
      Dellabella, A.; Andres, J. Ophthalmic toxicities of systemic drug therapy. US Pharm. 2015, 40, HS19HS24
    347. 347
      Epstein, D. L.; Grant, W. M. Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch. Ophthalmol. 1977, 95, 13781382,  DOI: 10.1001/archopht.1977.04450080088009
    348. 348
      Kim, J. H.; Kim, J. H.; Kim, K. W.; Kim, M. H.; Yu, Y. S. Intravenously administered gold nanoparticles pass through the blood–retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology 2009, 20, 505101,  DOI: 10.1088/0957-4484/20/50/505101
    349. 349
      Okamoto, N.; Ito, Y.; Nagai, N.; Murao, T.; Takiguchi, Y.; Kurimoto, T.; Mimura, O. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J. Oleo Sci. 2010, 59, 423430,  DOI: 10.5650/jos.59.423
    350. 350
      Almeida, H.; Amaral, M. H.; Lobao, P.; Silva, A. C.; Loboa, J. M. Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerations. J. Pharm. Pharm. Sci. 2014, 17, 278293,  DOI: 10.18433/J3DP43
    351. 351
      (a) Battaglia, L.; Serpe, L.; Foglietta, F.; Muntoni, E.; Gallarate, M.; Del Pozo Rodriguez, A.; Solinis, M. A. Application of lipid nanoparticles to ocular drug delivery. Expert Opin. Drug Delivery 2016, 13, 17431757,  DOI: 10.1080/17425247.2016.1201059 .
      (b) Willem de Vries, J.; Schnichels, S.; Hurst, J.; Strudel, L.; Gruszka, A.; Kwak, M.; Bartz-Schmidt, K. U.; Spitzer, M. S.; Herrmann, A. DNA nanoparticles for ophthalmic drug delivery. Biomaterials 2018, 157, 98106,  DOI: 10.1016/j.biomaterials.2017.11.046 .
      (c) Silva, M. M.; Calado, R.; Marto, J.; Bettencourt, A.; Almeida, A. J.; Goncalves, L. M. D. Chitosan nanoparticles as a mucoadhesive drug delivery system for ocular administration. Mar. Drugs 2017, 15, 370,  DOI: 10.3390/md15120370 .
      (d) Alvarez-Trabado, J.; Diebold, Y.; Sanchez, A. Designing lipid nanoparticles for topical ocular drug delivery. Int. J. Pharm. 2017, 532, 204217,  DOI: 10.1016/j.ijpharm.2017.09.017 .
      (e) Almeida, H.; Amaral, M. H.; Lobao, P.; Frigerio, C.; Sousa Lobo, J. M. Nanoparticles in ocular drug delivery systems for topical administration: promises and challenges. Curr. Pharm. Des. 2015, 21, 52125224,  DOI: 10.2174/1381612821666150923095155 .
      (f) Janagam, D. R.; Wu, L.; Lowe, T. L. Nanoparticles for drug delivery to the anterior segment of the eye. Adv. Drug Delivery Rev. 2017, 122, 3164,  DOI: 10.1016/j.addr.2017.04.001
    352. 352
      (a) Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained drug release in nanomedicine: a long-acting nanocarrier-based formulation for glaucoma. ACS Nano 2014, 8, 419429,  DOI: 10.1021/nn4046024 .
      (b) Reimondez-Troitino, S.; Csaba, N.; Alonso, M. J.; de la Fuente, M. Nanotherapies for the treatment of ocular diseases. Eur. J. Pharm. Biopharm. 2015, 95, 279293,  DOI: 10.1016/j.ejpb.2015.02.019
    353. 353
      (a) Kaur, I. P.; Garg, A.; Singla, A. K.; Aggarwal, D. Vesicular systems in ocular drug delivery: an overview. Int. J. Pharm. 2004, 269, 114,  DOI: 10.1016/j.ijpharm.2003.09.016 .
      (b) Sun, Y.; Fox, T.; Adhikary, G.; Kester, M.; Pearlman, E. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J. Leukocyte Biol. 2008, 83, 15121521,  DOI: 10.1189/jlb.0108076 .
      (c) Karn, P. R.; Kim, H. D.; Kang, H.; Sun, B. K.; Jin, S. E.; Hwang, S. J. Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion. Int. J. Nanomed. 2014, 9, 37913800,  DOI: 10.2147/IJN.S65601
    354. 354
      Shen, Y.; Tu, J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007, 9, E371,  DOI: 10.1208/aapsj0903044
    355. 355
      Abrishami, M.; Ghanavati, S. Z.; Soroush, D.; Rouhbakhsh, M.; Jaafari, M. R.; Malaekeh-Nikouei, B. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 2009, 29, 699703,  DOI: 10.1097/IAE.0b013e3181a2f42a
    356. 356
      Sahoo, S. K.; Dilnawaz, F.; Krishnakumar, S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008, 13, 144151,  DOI: 10.1016/j.drudis.2007.10.021
    357. 357
      Ge, X.; Wei, M.; He, S.; Yuan, W. E. Advances of non-ionic surfactant vesicles (Niosomes) and their application in drug delivery. Pharmaceutics 2019, 11, 55,  DOI: 10.3390/pharmaceutics11020055
    358. 358
      Mukherjee, B.; Patra, B.; Layek, B.; Mukherjee, A. Sustained release of acyclovir from nano-liposomes and nano-niosomes: an in vitro study. Int. J. Nanomed. 2007, 2, 213225
    359. 359
      Vyas, S. P.; Mysore, N.; Jaitely, V.; Venkatesan, N. Discoidal niosome based controlled ocular delivery of timolol maleate. Pharmazie 1998, 53, 466499
    360. 360
      Aggarwal, D.; Kaur, I. P. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system. Int. J. Pharm. 2005, 290, 155159,  DOI: 10.1016/j.ijpharm.2004.10.026
    361. 361
      Kaur, I. P.; Smitha, R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev. Ind. Pharm. 2002, 28, 353369,  DOI: 10.1081/DDC-120002997
    362. 362
      (a) Gaafar, P. M.; Abdallah, O. Y.; Farid, R. M.; Abdelkader, H. Preparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisolone. J. Liposome Res. 2014, 24, 204215,  DOI: 10.3109/08982104.2014.881850 .
      (b) Abdelkader, H.; Ismail, S.; Kamal, A.; Alany, R. G. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J. Pharm. Sci. 2011, 100, 18331846,  DOI: 10.1002/jps.22422
    363. 363
      (a) Abdelbary, G.; El-Gendy, N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 2008, 9, 740747,  DOI: 10.1208/s12249-008-9105-1 .
      (b) Ali, Y.; Lehmussaari, K. Industrial perspective in ocular drug delivery. Adv. Drug Delivery Rev. 2006, 58, 12581268,  DOI: 10.1016/j.addr.2006.07.022
    364. 364
      Schaumberg, D. A.; Dana, R.; Buring, J. E.; Sullivan, D. A. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch. Ophthalmol. 2009, 127, 763768,  DOI: 10.1001/archophthalmol.2009.103
    365. 365
      Novelia®, 2015; https://www.nemera.net/products/ophthalmic/novelia/ (accessed 2019-01-21).
    366. 366
      (a) Introducing Ocusurf Nanostructured Emulsion as a 505(B)(2) Strategy; On Drug Delivery: Lewes, UK, 2016; https://www.ondrugdelivery.com/introducing-ocusurf-nanostructured-emulsion-505b2-strategy/ (accessed 2019-02-21).
      (b) Kompella, U. B.; Kadam, R. S.; Lee, V. Recent advances in ophthalmic drug delivery. Ther. Delivery 2010, 1, 435456,  DOI: 10.4155/tde.10.40
    367. 367
      Ophthalmic Drug Delivery; On Drug Delivery: Lewes, UK, 2020; https://www.ondrugdelivery.com/publications/63/emultech.pdf/ (accessed 2019-01-21).
    368. 368
      (a) Faulds, D.; Goa, K. L.; Benfield, P. Cyclosporin. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993, 45, 9531040,  DOI: 10.2165/00003495-199345060-00007 .
      (b) Opsisporin: A Long Acting Drug Delivery Approach. MidaTech Pharma; On Drug Delivery: Lewes, UK, 2016; https://pdfs.semanticscholar.org/30f3/4f4261c25f00edab736c69463dacae1bdc91.pdf/ (accessed 2019-05-21).
    369. 369
      Mandal, A.; Bisht, R.; Rupenthal, I. D.; Mitra, A. K. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J. Controlled Release 2017, 248, 96116,  DOI: 10.1016/j.jconrel.2017.01.012
    370. 370
      Yuan, X.; Marcano, D. C.; Shin, C. S.; Hua, X.; Isenhart, L. C.; Pflugfelder, S. C.; Acharya, G. Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano 2015, 9, 17491758,  DOI: 10.1021/nn506599f
    371. 371
      (a) Than, A.; Liu, C.; Chang, H.; Duong, P. K.; Cheung, C. M. G.; Xu, C.; Wang, X.; Chen, P. Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. Nat. Commun. 2018, 9, 4433,  DOI: 10.1038/s41467-018-06981-w .
      (b) Lowder, C. Y.; Hollander, D. A. Review of the drug-infused eye implant - ozurdex (dexamethasone intravitreal implant). US Ophthal. Rev. 2011, 4, 107112,  DOI: 10.17925/USOR.2011.04.02.107
    372. 372
      INVELTYS (Loteprednol Etabonate Ophthalmic Suspension) 1%; Kala Pharmaceuticals, 2019; https://inveltys.com/ (accessed 2020-03-20).
    373. 373
      Dextenza; Ocular Therapeutix: Bedford, MA, 2020; https://www.ocutx.com/products/dextenza/ (accessed 2020-03-20).
    374. 374
      (a) Kapoor, K. G.; Wagner, M. G.; Wagner, A. L. The sustained-release dexamethasone implant: expanding indications in vitreoretinal disease. Semin. Ophthalmol. 2015, 30, 475481,  DOI: 10.3109/08820538.2014.889179 .
      (b) London, N. J.; Chiang, A.; Haller, J. A. The dexamethasone drug delivery system: indications and evidence. Adv. Ther. 2011, 28, 351366,  DOI: 10.1007/s12325-011-0019-z
    375. 375
      Boyer, D. S.; Yoon, Y. H.; Belfort, R.; Bandello, F.; Maturi, R. K.; Augustin, A. J.; Li, X. Y.; Cui, H.; Hashad, Y.; Whitcup, S. M. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014, 121, 19041914,  DOI: 10.1016/j.ophtha.2014.04.024
    376. 376
      OZURDEX (Dexamethasone Intravitreal Implant), 2020; http://www.ozurdex.com/ (accessed Jan10, 2020).
    377. 377
      (a) Matonti, F.; Pommier, S.; Meyer, F.; Hajjar, C.; Merite, P. Y.; Parrat, E.; Rouhette, H.; Rebollo, O.; Guigou, S. Long-term efficacy and safety of intravitreal dexamethasone implant for the treatment of diabetic macular edema. Eur. J. Ophthalmol. 2016, 26, 454459,  DOI: 10.5301/ejo.5000787 .
      (b) Pareja-Ríos, A.; Ruiz-de la Fuente-Rodríguez, P.; Bonaque-González, S.; López-Gálvez, M.; Lozano-López, V.; Romero-Aroca, P. Intravitreal dexamethasone implants for diabetic macular edema. Int. J. Ophthalmol. 2018, 11, 7782,  DOI: 10.18240/ijo.2018.01.14 .
      (c) Iglicki, M.; Busch, C.; Zur, D.; Okada, M.; Mariussi, M.; Chhablani, J. K.; Cebeci, Z.; Fraser-Bell, S.; Chaikitmongkol, V.; Couturier, A.; Giancipoli, E.; Lupidi, M.; Rodríguez-Valdés, P. J.; Rehak, M.; Fung, A. T.; Goldstein, M.; Loewenstein, A. dexamethasone implant for diabetic macular edema in naïve compared with refractory eyes: The International Retina Group Real-Life 24 month multicenter study. the irgrel-dex study. Retina 2019, 39, 4451,  DOI: 10.1097/IAE.0000000000002196
    378. 378
      Menezo, M.; Roca, M.; Menezo, V.; Pascual, I. Intravitreal dexamethasone implant ozurdex® in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: A prospective 12-month followup study. Curr. Med. Res. Opin. 2019, 35, 21112116,  DOI: 10.1080/03007995.2019.1652449
    379. 379
      Errera, M. H.; Westcott, M.; Benesty, J.; Falah, S.; Smadja, J.; Orès, R.; Pratas, A. C.; Sedira, N.; Bensemlali, A.; Héron, E.; Goldschmidt, P.; Bodaghi, B.; Sahel, J. A. Comparison of the dexamethasone implant (ozurdex®) and inferior fornix-based sub-tenon yriamcinolone acetonide for treatment of inflammatory ocular diseases. Ocul. Immunol. Inflammation 2019, 27, 319329,  DOI: 10.1080/09273948.2018.1501492
    380. 380
      (a) Khurana, R. N.; Porco, T. C. Efficacy and safety of dexamethasone intravitreal implant for persistent uveitis cystoid macular edema. Retina 2015, 35, 16401646,  DOI: 10.1097/IAE.0000000000000515 .
      (b) Cao, J. H.; Mulvahill, M.; Zhang, L.; Joondeph, B. C.; Dacey, M. S. Dexamethasone intravitreal implant in the treatment of persistent uveitis macular edema in the absence of active inflammation. Ophthalmology 2014, 121, 18711876,  DOI: 10.1016/j.ophtha.2014.04.012 .
      (c) Bratton, M. L.; He, Y. G.; Weakley, D. R. Dexamethasone intravitreal implant (ozurdex) for the treatment of pediatric uveitis. J. AAPOS. 2014, 18, 110113,  DOI: 10.1016/j.jaapos.2013.11.014
    381. 381
      Ilhan, N.; Coskun, M.; Ilhan, O.; Tuzco, E. A.; Daglıoglu, M. C.; Elbeyli, A.; Keskin, U.; Oksuz, H. Effect of intravitreal injection of dexamethasone implant on corneal endothelium in macular edema due to retinal vein occlusion. Cutaneous Ocul. Toxicol. 2015, 34, 294297,  DOI: 10.3109/15569527.2014.975242
    382. 382
      Güler, H. A.; Örnek, N.; Örnek, K.; Büyüktortop Gökçinar, N.; Oğurel, T.; Yumuşak, M. E.; Onaran, Z. Effect of dexamethasone intravitreal implant (Ozurdex®) on corneal endothelium in retinal vein occlusion patients. BMC Ophthalmol. 2018, 18, 235,  DOI: 10.1186/s12886-018-0905-0
    383. 383
      Phulke, S.; Kaushik, S.; Kaur, S.; Pandav, S. S. Steroid-induced glaucoma: an avoidable irreversible blindness. J. Curr. Glaucoma Pract. 2017, 11, 6772,  DOI: 10.5005/jp-journals-10028-1226
    384. 384
      Dot, C.; El Chehab, H.; Russo, A.; Agard, E. Ocular hypertension after intravitreal steroid injections: clinical update as of 2015. J. Fr. Ophtalmol. 2015, 38, 656664,  DOI: 10.1016/j.jfo.2015.03.002
    385. 385
      Sharma, A.; Kuppermann, B. D.; Bandello, F.; Lanzetta, P.; Zur, D.; Park, S. W.; Yu, H. G., Saravanan, V. R.; Zacharias, L. C.; Barreira, A. K.; Iglicki, M.; Miassi, F.; Veritti, D.; Tsao, S.; Makam, D.; Jain, N.; Loewenstein, A. Intraocular pressure (IOP) after intravitreal dexamethasone implant (ozurdex) amongst different geographic populations-geodex-iop study. Eye 2019,  DOI: 10.1038/s41433-019-0616-7 .
    386. 386
      Woodward, D. F.; Phelps, R. L.; Krauss, A. H.; Weber, A.; Short, B.; Chen, J.; Liang, Y.; Wheeler, L. A. Bimatoprost: a novel antiglaucoma agent. Cardiovasc. Drug Rev. 2004, 22, 103,  DOI: 10.1111/j.1527-3466.2004.tb00134.x
    387. 387
      (a) Eisenberg, D. L.; Toris, C. B.; Camras, C. B. Bimatoprost and travoprost: a review of recent studies of two new glaucoma drugs. Surv. Ophthalmol. 2002, 47, S105S115,  DOI: 10.1016/S0039-6257(02)00327-2 .
      (b) Orzalesi, N.; Rossetti, L.; Bottoli, A.; Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology 2006, 113, 239246,  DOI: 10.1016/j.ophtha.2005.10.045
    388. 388
      Kammer, J. A.; Katzman, B.; Ackerman, S.; Hollander, D. Efficacy and tolerability of bimatoprost versus travoprost in patients previously on latanoprost: a 3-month, randomised, masked-evaluator, multicentre study. Br. J. Ophthalmol. 2010, 94, 7479,  DOI: 10.1136/bjo.2009.158071
    389. 389
      Maulvi, F. A.; Soni, T. G.; Shah, D. O. A review on therapeutic contact lenses for ocular drug delivery. Drug Delivery 2016, 23, 30173026,  DOI: 10.3109/10717544.2016.1138342
    390. 390
      (a) Maulvi, F. A.; Soni, F. A.; Shah, D. O. Effect of timolol maleate concentration on uptake and release from hydrogel contact lenses using soaking method. J. Pharm. Appl. Sci. 2014, 1, 1723.
      (b) Carvalho, I. M.; Marques, C. S.; Oliveira, R. S.; Coelho, P. B.; Costa, P. C.; Ferreira, D. C. Sustained drug release by contact lenses for glaucoma treatment - a review. J. Controlled Release 2015, 202, 7682,  DOI: 10.1016/j.jconrel.2015.01.023 .
      (c) Guzman-Aranguez, A.; Colligris, B.; Pintor, J. Contact lenses: promising devices for ocular drug delivery. J. Ocul. Pharmacol. Ther. 2013, 29, 189199,  DOI: 10.1089/jop.2012.0212
    391. 391
      Xu, W.; Jiao, W.; Li, S.; Tao, X.; Mu, G. Bimatoprost loaded microemulsion laden contact lens to treat glaucoma. J. Drug Delivery Sci. Technol. 2019, 54, 101330,  DOI: 10.1016/j.jddst.2019.101330
    392. 392
      Yadav, M.; Guzman-Aranguez, A.; Perez de Lara, M. J.; Singh, M.; Singh, J.; Kaur, I. P. Bimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: in vitro and in vivo evaluation. Mater. Sci. Eng., C 2019, 103, 109730,  DOI: 10.1016/j.msec.2019.05.015
    393. 393
      Lee, S. S.; Hughes, P.; Ross, A. D.; Robinson, M. R. Biodegradable implants for sustained drug release in the eye. Pharm. Res. 2010, 27, 20432053,  DOI: 10.1007/s11095-010-0159-x
    394. 394
      Lewis, R. A.; Christie, W. C.; Day, D. G.; Craven, E. R.; Walters, T.; Bejanian, M.; Lee, S. S.; Goodkin, M. L.; Zhang, J.; Whitcup, S. M.; Robinson, M. R.; Aung, T.; Beck, A. D.; Christie, W. C.; Coote, M.; Crane, C. J.; Craven, E. R.; Crichton, A.; Day, D. G.; Durcan, F. J.; Flynn, W. J.; Gagne, S.; Goldberg, D. F.; Jinapriya, D.; Johnson, C. S.; Kurtz, S.; Lewis, R. A.; Mansberger, S. L.; Perera, S. A.; Rotberg, M. H.; Saltzmann, R. M.; Schenker, H. I.; Tepedino, M. E.; Yap-Veloso, M. I. R.; Uy, H. S.; Walters, T. R. Bimatoprost sustained-release implants for glaucoma therapy: 6-month results from a phase I/II clinical trial. Am. J. Ophthalmol. 2017, 175, 137147,  DOI: 10.1016/j.ajo.2016.11.020
    395. 395
      Lee, S. S.; Dibas, M.; Almazan, A.; Robinson, M. R. Dose–response of intracameral bimatoprost sustained-release implant and topical bimatoprost in lowering intraocular pressure. J. Ocul. Pharmacol. Ther. 2019, 35, 138144,  DOI: 10.1089/jop.2018.0095
    396. 396
      Seal, J. R.; Robinson, M. R.; Burke, J.; Bejanian, M.; Coote, M.; Attar, M. Intracameral sustained-release bimatoprost implant delivers bimatoprost to target tissues with reduced drug exposure to off-target tissues. J. Ocul. Pharmacol. Ther. 2019, 35, 5057,  DOI: 10.1089/jop.2018.0067
    397. 397
      U.S. FDA Accepts Allergan’s New Drug Application for Bimatoprost Sustained-Release in Patients with Open-Angle Glaucoma or Ocular Hypertension; U.S. Food and Drug Administration, 2019; https://www.prnewswire.com/news-releases/us-fda-accepts-allergans-new-drug-application-for-bimatoprost-sustained-release-in-patients-with-open-angle-glaucoma-or-ocular-hypertension-300886238.html (accessed Dec 19, 2019).
    398. 398
      (a) Jervis, L. P. A summary of recent advances in ocular inserts and implants. J. Bioequivalence Bioavailability 2016, 9, 320323,  DOI: 10.4172/jbb.1000318 .
      (b) Gote, V.; Sikder, S.; Sicotte, J.; Pal, D. Ocular drug delivery: present innovations and future challenges. J. Pharmacol. Exp. Ther. 2019, 370, 602624,  DOI: 10.1124/jpet.119.256933 .
      (c) Gote, V.; Pal, D. Ocular implants in the clinic and under clinical investigation for ocular disorders. EC Opthalmol. 2019, 10.8, 660666

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